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Publication numberUS7572812 B2
Publication typeGrant
Application numberUS 11/337,271
Publication dateAug 11, 2009
Filing dateJan 20, 2006
Priority dateJul 24, 2003
Fee statusPaid
Also published asCA2533509A1, CA2533509C, CN1829708A, CN101914088A, DE602004020994D1, EP1648878A1, EP1648878B1, EP1648878B9, EP2067776A1, US8349842, US20060199824, US20100210686, WO2005009987A1
Publication number11337271, 337271, US 7572812 B2, US 7572812B2, US-B2-7572812, US7572812 B2, US7572812B2
InventorsQun Sun, Kate Xin Wen, Xiaoming Zhou
Original AssigneePurdue Pharma, L.P., Usa
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Therapeutic agents useful for treating pain
US 7572812 B2
Abstract
Piperidine Compounds; compositions comprising a Piperidine Compound; and methods for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal comprising administering to an animal in need thereof an effective amount of a Piperidine Compound are disclosed. In one embodiment, the Piperidine Compound has the formula:

and pharmaceutically acceptable salts thereof, wherein Ar1, Ar2, X, R3, R4, and m are as disclosed herein.
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Claims(87)
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
Ar1 is
X is O, S, N—CN, N—OH, or N—OR10;
R1 is —H, -halo, —CH3, —NO2, —CN, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —OH, —CN, —NO2, or —NH2;
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, —CN, —OH, —NO2, or —NH2;
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —OR10, —SR13, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —CON(R13)2, —SO2R10, or —NO2;
each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;
each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C8)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or S(O)2R7;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R8 and R9 are independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
R10 is —(C1-C4)alkyl;
each R13 is independently:
(a) —H, or —(C1-C4)alkyl; or
(b) -phenyl or -(3- to 5-membered)heteroaryl each of which is unsubstituted or substituted with one or more R6 groups;
each R14 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each halo is independently —F, —Cl, —Br, or —I;
n is an integer ranging from 0 to 3;
q is an integer ranging from 0 to 4; and
m is 0 or 1.
2. The compound of claim 1, wherein X is O and R4 is -halo or —OH.
3. The compound of claim 2, wherein m is 0, and n is 0.
4. The compound of claim 3, wherein R1 is —CH3, —C(halo)3, or -halo.
5. The compound of claim 4, wherein Ar2 is
6. The compound of claim 5, wherein R8 is —H and R9 is —H, a —(C1-C6)alkyl group, -halo, —C(halo)3, or —OR7.
7. A compound of formula (II):
or a pharmaceutically acceptable salt thereof, wherein
Ar3 is
X is O, S, N—CN, N—OH, or N—OR10;
R1 is -halo, —CH3, —NO2, —CN, —OH, —OCH3, —NH2, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R2 is independently:
(a) -halo, —OH, or —NH2,
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, (C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, —CN, —OH, —NO2, or —NH2;
(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, (C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or
(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —OR10, —SR13, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —SO2R10, or —NO2;
each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CHNR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;
each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or —CH2(halo);
each R9 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;
R10 is —(C1-C4)alkyl;
each R11 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;
each R13 is independently:
(a) —H or —(C1-C4)alkyl; or
(b) -phenyl or -(3- to 5-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each halo is independently —F, —Cl, —Br, or —I;
n is an integer ranging from 0 to 3;
r is an integer ranging from 0 to 6;
s is an integer ranging from 0 to 5; and
m is 0 or 1.
8. The compound of claim 7, wherein X is 0 and R4 is -halo or —OH.
9. The compound of claim 8, wherein R1 is —CH3, —C(halo)3, or -halo.
10. The compound of claim 9, wherein Ar3 is
11. The compound of claim 10, wherein s is 1 and R9 is at the 4-position of the phenyl ring.
12. The compound of claim 10, wherein R9 is a —(C1-C6)alkyl group, -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, or —OCF3.
13. The compound of claim 12, wherein R9 is an -iso-propyl, -tert-butyl, -iso-butyl, or -sec-butyl group.
14. A composition comprising the compound or a phannaceutically acceptable salt of the compound of claim 1 and a phannaceutically acceptable carrier or excipient.
15. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 7 and a pharmaceutically acceptable carrier or excipient.
16. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 and optionally an effective amount of another therapeutic agent.
17. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 7 and optionally an effective amount of another therapeutic agent.
18. The compound of claim 2, wherein R4 is —F.
19. The compound of claim 4, wherein R1 is —CF3, —F, or —Cl.
20. The compound of claim 6, wherein R9 is -iso-propyl, -iso-butyl, -sec-butyl, -tert-butyl, —F, —Cl, —CF3, —OCH3, —OCH2CH3, or —OCF3.
21. The compound of claim 8, wherein R4 is —F.
22. The compound of claim 9, wherein R1 is —CF3, —F, or —Cl.
23. The compound of claim 2, wherein m is 0, n is 1, and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
24. The compound of claim 23, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
25. The compound of claim 23, wherein R1 is —CH3, —C(halo)3, or -halo.
26. The compound of claim 25, wherein R1 is —CF3, —F, or —Cl.
27. The compound of claim 25, wherein Ar2 is
28. The compound of claim 27, wherein R8 is —H and R9 is —H, a —(C1-C6)alkyl group, -halo, —C(halo)3, or —OR7.
29. The compound of claim 28, wherein R9 is -iso-propyl, -iso-butyl, -sec-butyl, -tert-butyl, —F, —Cl, —CF3, —OCH3, —OCH2CH3, or —OCF3.
30. The compound of claim 24, wherein R1 is —CH3, —C(halo)3, or -halo.
31. The compound of claim 30, wherein R1 is —CF3, —F, or —Cl.
32. The compound of claim 30, wherein Ar2 is
33. The compound of claim 32, wherein R8 is —H and R9 is —H, a —(C1-C6)alkyl group, -halo, —C(halo)3, or —OR7.
34. The compound of claim 33, wherein R9 is -iso-propyl, -iso-butyl, -sec-butyl, -tert-butyl, —F, —Cl, —CF3. —OCH3, —OCH2CH3, or —OCF3.
35. The compound of claim 2, wherein m is 1, R3 is —CH3, n is 1, and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
36. The compound of claim 35, wherein R2 is —(C1-C10)alkyl substituted with two R5 groups.
37. The compound of claim 35, wherein R1 is —CH3, —C(halo)3, or -halo.
38. The compound of claim 35, wherein R1 is —CF3, —F, or —Cl.
39. The compound of claim 37, wherein Ar2 is
40. The compound of claim 39, wherein R8 is —H and R9 is —H, a —(C1-C6)alkyl group, -halo, —C(halo)3, or —OR7.
41. The compound of claim 40, wherein R9 is -iso-propyl, -iso-butyl, -sec-butyl, -tert-butyl, —F, —Cl, —CF3, —OCH3, —OCH2CH3, or —OCF3.
42. The compound of claim 4, wherein Ar2 is
43. The compound of claim 42, wherein each R14 is independently —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —C(halo)3, -halo, or —OR7.
44. The compound of claim 43, wherein q is 1.
45. The compound of claim 25, wherein Ar2 is
46. The compound of claim 45, wherein each R14 is independently —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —C(halo)3, -halo, or —OR7.
47. The compound of claim 46, wherein q is 1.
48. The compound of claim 30, wherein Ar2 is
49. The compound of claim 48, wherein each R14 is independently —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —C(halo)3, -halo, or —OR7.
50. The compound of claim 49, wherein q is 1.
51. The compound of claim 37, wherein Ar2 is
52. The compound of claim 51, wherein each R14 is independently —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —C(halo)3, -halo, or —OR7.
53. The compound of claim 52, wherein q is 1.
54. The compound of claim 4, wherein Ar2 is
55. The compound of claim 54, wherein each R14 is independently —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —C(halo)3, -halo, or —OR7.
56. The compound of claim 55, wherein q is 1.
57. The compound of claim 25, wherein Ar2 is
58. The compound of claim 57, wherein each R14 is independently —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —C(halo)3, -halo, or —OR7.
59. The compound of claim 58, wherein q is 1.
60. The compound of claim 30, wherein Ar2 is
61. The compound of claim 60, wherein each R14 is independently —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —C(halo)3, -halo, or —OR7.
62. The compound of claim 61, wherein q is 1.
63. The compound of claim 37, wherein Ar2 is
64. The compound of claim 63, wherein each R14 is independently —(C1-C6)alkyl, —(C3-C8)cycloalkyl, —C(halo)3, -halo, or —OR7.
65. The compound of claim 64, wherein q is 1.
66. The compound of claim 11, wherein m is 0.
67. The compound of claim 66, wherein n is 0.
68. The compound of claim 66, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
69. The compound of claim 68, wherein R2 is —(C1-C10)alkyl which is substituted with two R5 groups.
70. The compound of claim 11, wherein m is 1 and R3 is —CH3.
71. The compound of claim 70, wherein n is 0.
72. The compound of claim 70, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicyctoalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
73. The compound of claim 72, wherein R2 is —(C1-C10)alkyl which is substituted with two R5 groups.
74. The compound of claim 10, wherein R9 is a —(C1-C6)alkyl group, -halo, -cyclohexyl, -tert-butoxy, -iso-propoxy, —CF3, or —OCF3 and an R9 group, when present, is substituted at the 4-position of the phenyl ring.
75. The compound of claim 74, wherein R9 is an -iso-propyl, -tert-butyl, -iso-butyl, or -sec-butyl group and an R9 group.
76. The compound of claim 74, wherein m is 0.
77. The compound of claim 76, wherein n is 0.
78. The compound of claim 76, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7- membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
79. The compound of claim 78, wherein R2 is —(C1-C10)alkyl which is substituted with two R5 groups.
80. The compound of claim 74, wherein m is 1 and R3 is —CH3.
81. The compound of claim 80, wherein n is 0.
82. The compound of claim 80, wherein n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.
83. The compound of claim 82, wherein R2 is —(C1-C10)alkyl which is substituted with two R5 groups.
84. An in vitro method for inhibiting VR1 function in a cell comprising:
contacting a cell expressing VR1 in vitro with a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.
85. A method of treating pain in an animal, comprising:
administering to an animal in need of treatment for pain a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount ranging from 0.01 mg/kg body weight to 2500 mg/kg body weight;
wherein said compound is capable of reducing pain as or more effectively than a similar dose of one or more of the positive control analgesics celecoxib, indomethacin, or naproxen, as measured by one or more of the in vivo pain tests consisting of an acute pain test, an inflammatory pain test, a neuropathic pain test, a mechanical stimuli pain test, a thermal stimuli pain test, or a tactile allodynia test.
86. An in vitro method for inhibiting VR1 function in a cell comprising:
contacting a cell expressing VR1 in vitro with a compound of claim 7, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce calcium ion mobilization into said cell treated with an activator of VR1 as compared to said cell expressing VR1 in vitro treated with an activator of VR1 and not contacted with said compound.
87. A method of treating pain in an animal, comprising:
administering to an animal in need of treatment for pain a compound of claim 7, or a pharmaceutically acceptable salt thereof, in an amount ranging from 0.01 mg/kg body weight to 2500 mg/kg body weight;
wherein said compound is capable of reducing pain as or more effectively than a similar dose of one or more of the positive control analgesics celecoxib, indomethacin, or naproxen, as measured by one or more of the in vivo pain tests consisting of an acute pain test, an inflammatory pain test, a neuropathic pain test, a mechanical stimuli pain test, a thermal stimuli pain test, or a tactile allodynia test.
Description

This application is a continuation of and claims the benefit of International patent application no. PCT/US2004/023912, filed Jul. 23, 2004, which claims the benefit of U.S. provisional application No. 60/489,515, filed Jul. 24, 2003, the disclosure of each application being incorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

The present invention relates to Piperidine Compounds, compositions comprising an effective amount of a Piperidine Compound and methods for treating or preventing a condition such as pain comprising administering to an animal in need thereof an effective amount of a Piperidine Compound.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical advice and treatment. Pain can be acute or chronic. While acute pain is usually self-limited, chronic pain persists for 3 months or longer and can lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed. 1996)).

Moreover, chronic pain can be classified as either nociceptive or neuropathic. Nociceptive pain includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Neuropathic pain is caused by damage to the peripheral or central nervous system and is maintained by aberrant somatosensory processing. There is a large body of evidence relating activity at both Group I metabatropic glutamate receptors (mGluRs) (M. E. Fundytus, CNS Drugs 15:29-58 (2001)) and vanilloid receptors (V. Di Marzo et al., Current Opinion in Neurobiology 12:372-379 (2002)) to pain processing. Inhibiting mGluR1 or mGluR5 reduces pain, as shown by in vivo treatment with antibodies selective for either mGluR1 or mGluR5, where neuropathic pain in rats was attenuated (M. E. Fundytus et al., NeuroReport 9:731-735 (1998)). It has also been shown that antisense oligonucleotide knockdown of mGluR1 alleviates both neuropathic and inflammatory pain (M. E. Fundytus et al., British Journal of Pharmacology 132:354-367 (2001); M. E. Fundytus et al., Pharmacology, Biochemsitry & Behavior 73:401-410 (2002)). Small molecule antagonists for mGluR5-attenuated pain in vivo animal models are disclosed in, e.g., K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrul et al., Neuroscience Letters 292:115-118 (2000).

Nociceptive pain has been traditionally managed by administering non-opioid analgesics, such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, and naproxen; or opioid analgesics, including morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. In addition to the above-listed treatments, neuropathic pain, which can be difficult to treat, has also been treated with anti-epileptics (e.g., gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDA antagonists (e.g., ketamine, dextromethorphan), topical lidocaine (for post-herpetic neuralgia), and tricyclic antidepressants (e.g., fluoxetine, sertraline and amitriptyline).

UI is uncontrollable urination, generally caused by bladder-detrusor-muscle instability. UI affects people of all ages and levels of physical health, both in health care settings and in the community at large. Physiologic bladder contraction results in large part from acetylcholine-induced stimulation of post-ganglionic muscarinic-receptor sites on bladder smooth muscle. Treatments for UI include the administration of drugs having bladder-relaxant properties, which help to control bladder-detrusor-muscle overactivity. For example, anticholinergics such as propantheline bromide and glycopyrrolate, and combinations of smooth-muscle relaxants such as a combination of racemic oxybutynin and dicyclomine or an anticholinergic, have been used to treat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995); Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J. 63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)). These drugs are not effective, however, in all patients having uninhibited bladder contractions. Administration of anticholinergic medications represent the mainstay of this type of treatment.

None of the existing commercial drug treatments for UI has achieved complete success in all classes of UI patients, nor has treatment occurred without significant adverse side effects. For example, drowsiness, dry mouth, constipation, blurred vision, headaches, tachycardia, and cardiac arrhythmia, which are related to the anticholinergic activity of traditional anti-UI drugs, can occur frequently and adversely affect patient compliance. Yet despite the prevalence of unwanted anticholinergic effects in many patients, anticholinergic drugs are currently prescribed for patients having UI. The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997).

Ulcers are sores occurring where the lining of the digestive tract has been eroded by stomach acids or digestive juices. The sores are typically well-defined round or oval lesions primarily occurring in the stomach and duodenum. About 1 in 10 people develop an ulcer. Ulcers develop as a result of an imbalance between acid-secretory factors, also known as “aggressive factors,” such as stomach acid, pepsin, and Helicobacter pylori infection, and local mucosal-protective factors, such as secretion of bicarbonate, mucus, and prostaglandins.

Treatment of ulcers typically involves reducing or inhibiting the aggressive factors. For example, antacids such as aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can be used to neutralize stomach acids. Antacids, however, can cause alkalosis, leading to nausea, headache, and weakness. Antacids can also interfere with the absorption of other drugs into the blood stream and cause diarrhea.

H2 antagonists, such as cimetidine, ranitidine, famotidine, and nizatidine, are also used to treat ulcers. H2 antagonists promote ulcer healing by reducing gastric acid and digestive-enzyme secretion elicited by histamine and other H2 agonists in the stomach and duodenum. H2 antagonists, however, can cause breast enlargement and impotence in men, mental changes (especially in the elderly), headache, dizziness, nausea, myalgia, diarrhea, rash, and fever.

H+, K+-ATPase inhibitors such as omeprazole and lansoprazole are also used to treat ulcers. H+, K+-ATPase inhibitors inhibit the production of enzymes used by the stomach to secrete acid. Side effects associated with H+, K+-ATPase inhibitors include nausea, diarrhea, abdominal colic, headache, dizziness, somnolence, skin rashes, and transient elevations of plasma activities of aminotransferases.

Sucraflate is also used to treat ulcers. Sucraflate adheres to epithelial cells and is believed to form a protective coating at the base of an ulcer to promote healing. Sucraflate, however, can cause constipation, dry mouth, and interfere with the absorption of other drugs.

Antibiotics are used when Helicobacter pylori is the underlying cause of the ulcer. Often antibiotic therapy is coupled with the administration of bismuth compounds such as bismuth subsalicylate and colloidal bismuth citrate. The bismuth compounds are believed to enhance secretion of mucous and HCO3 , inhibit pepsin activity, and act as an antibacterial against H. pylori. Ingestion of bismuth compounds, however, can lead to elevated plasma concentrations of Bi+3 and can interfere with the absorption of other drugs.

Prostaglandin analogues, such as misoprostal, inhibit secretion of acid and stimulate the secretion of mucous and bicarbonate and are also used to treat ulcers, especially ulcers in patients who require nonsteroidal anti-inflammatory drugs. Effective oral doses of prostaglandin analogues, however, can cause diarrhea and abdominal cramping. In addition, some prostaglandin analogues are abortifacients.

Carbenoxolone, a mineral corticoid, can also be used to treat ulcers. Carbenoxolone appears to alter the composition and quantity of mucous, thereby enhancing the mucosal barrier. Carbenoxolone, however, can lead to Na+ and fluid retention, hypertension, hypokalemia, and impaired glucose tolerance.

Muscarinic cholinergic antagonists such as pirenzapine and telenzapine can also be used to reduce acid secretion and treat ulcers. Side effects of muscarinic cholinergic antagonists include dry mouth, blurred vision, and constipation. The Merck Manual of Medical Information 496-500 (R. Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis of Therapeutics 901-915 (J. Hardman and L. Limbird eds., 9th ed. 1996).

Inflammatory-bowel disease (“IBD”) is a chronic disorder in which the bowel becomes inflamed, often causing recurring abdominal cramps and diarrhea. The two types of IBD are Crohn's disease and ulcerative colitis.

Crohn's disease, which can include regional enteritis, granulomatous ileitis, and ileocolitis, is a chronic inflammation of the intestinal wall. Crohn's disease occurs equally in both sexes and is more common in Jews of eastern-European ancestry. Most cases of Crohn's disease begin before age 30 and the majority start between the ages of 14 and 24. The disease typically affects the full thickness of the intestinal wall. Generally the disease affects the lowest portion of the small intestine (ileum) and the large intestine, but can occur in any part of the digestive tract.

Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominal pain, fever, loss of appetite, and weight loss. Complications associated with Crohn's disease include the development of intestinal obstructions, abnormal connecting channels (fistulas), and abscesses. The risk of cancer of the large intestine is increased in people who have Crohn's disease. Often Crohn's disease is associated with other disorders such as gallstones, inadequate absorption of nutrients, amyloidosis, arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyoderma gangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primary sclerosing cholangitis. There is no known cure for Crohn's disease.

Cramps and diarrhea, side effects associated with Crohn's disease, can be relieved by anticholinergic drugs, diphenoxylate, loperamide, deodorized opium tincture, or codeine. Generally, the drug is taken orally before a meal.

Broad-spectrum antibiotics are often administered to treat the symptoms of Crohn's disease. The antibiotic metronidazole is often administered when the disease affects the large intestine or causes abscesses and fistulas around the anus. Long-term use of metronidazole, however, can damage nerves, resulting in pins-and-needles sensations in the arms and legs. Sulfasalazine and chemically related drugs can suppress mild inflammation, especially in the large intestine. These drugs, however, are less effective in sudden, severe flare-ups. Corticosteroids, such as prednisone, reduce fever and diarrhea and relieve abdominal pain and tenderness. Long-term corticosteroid therapy, however, invariably results in serious side effects such as high blood-sugar levels, increased risk of infection, osteoporosis, water retention, and fragility of the skin. Drugs such as azathioprine and mercaptourine can compromise the immune system and are often effective for Crohn's disease in patients that do not respond to other drugs. These drugs, however, usually need 3 to 6 months before they produce benefits and can cause serious side effects such as allergy, pancreatitis, and low white-blood-cell count.

When Crohn's disease causes the intestine to be obstructed or when abscesses or fistulas do not heal, surgery can be necessary to remove diseased sections of the intestine. Surgery, however, does not cure the disease, and inflammation tends to recur where the intestine is rejoined. In almost half of the cases a second operation is needed. The Merck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestine becomes inflamed and ulcerated, leading to episodes of bloody diarrhea, abdominal cramps, and fever. Ulcerative colitis usually begins between ages 15 and 30; however, a small group of people have their first attack between ages 50 and 70. Unlike Crohn's disease, ulcerative colitis never affects the small intestine and does not affect the full thickness of the intestine. The disease usually begins in the rectum and the sigmoid colon and eventually spreads partially or completely throughout the large intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation, reducing symptoms, and replacing lost fluids and nutrients. Anticholinergic drugs and low doses of diphenoxylate or loperamide are administered for treating mild diarrhea. For more intense diarrhea higher doses of diphenoxylate or loperamide, or deodorized opium tincture or codeine are administered. Sulfasalazine, olsalazie, prednisone, or mesalamine can be used to reduce inflammation. Azathioprine and mercaptopurine have been used to maintain remissions in ulcerative-colitis patients who would otherwise need long-term corticosteroid treatment. In severe cases of ulcerative colitis the patient is hospitalized and given corticosteroids intravenously. People with severe rectal bleeding can require transfusions and intravenous fluids. If toxic colitis develops and treatments fail, surgery to remove the large intestine can be necessary. Non-emergency surgery can be performed if cancer is diagnosed, precancerous legions are detected, or unremitting chronic disease would otherwise make the person an invalid or dependent on high doses of corticosteroids. Complete removal of the large intestine and rectum permanently cures ulcerative colitis. The Merck Manual of Medical Information 530-532 (R. Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis of Therapeutics (J. Hardman and L. Limbird eds., 9th ed. 1996).

Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entire gastrointestinal tract, causing abdominal pain, constipation, and/or diarrhea. IBS affects three-times more women than men. In IBS stimuli such as stress, diet, drugs, hormones, or irritants can cause the gastrointestinal tract to contract abnormally. During an episode of IBS, contractions of the gastrointestinal tract become stronger and more frequent, resulting in the rapid transit of food and feces through the small intestine, often leading to diarrhea. Cramps result from the strong contractions of the large intestine and increased sensitivity of pain receptors in the large intestine.

There are two major types of IBS. The first type, spastic-colon type, is commonly triggered by eating, and usually produces periodic constipation and diarrhea with pain. Mucous often appears in the stool. The pain can come in bouts of continuous dull aching pain or cramps, usually in the lower abdomen. The person suffering from spastic-colon type IBS can also experience bloating, gas, nausea, headache, fatigue, depression, anxiety, and difficulty concentrating. The second type of IBS usually produces painless diarrhea or constipation. The diarrhea can begin suddenly and with extreme urgency. Often the diarrhea occurs soon after a meal and can sometimes occur immediately upon awakening.

Treatment of IBS typically involves modification of an IBS-patient's diet. Often it is recommended that an IBS patient avoid beans, cabbage, sorbitol, and fructose. A low-fat, high-fiber diet can also help some IBS patients. Regular physical activity can also help keep the gastrointestinal tract functioning properly. Drugs such as propantheline that slow the function of the gastrointestinal tract are generally not effective for treating IBS. Antidiarrheal drugs, such as diphenoxylate and loperamide, help with diarrhea. The Merck Manual of Medical Information 525-526 (R. Berkow ed., 1997).

Certain pharmaceutical agents have been administered for treating addiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use of nontoxic NMDA-blocking agents co-administered with an addictive substance to prevent the development of tolerance or withdrawal symptoms. U.S. Pat. No. 5,574,052 to Rose et al. discloses co-administration of an addictive substance with an antagonist to partially block the pharmacological effects of the addictive substance. U.S. Pat. No. 5,075,341 to Mendelson et al. discloses the use of a mixed opiate agonist/antagonist to treat cocaine and opiate addiction. U.S. Pat. No. 5,232,934 to Downs discloses administration of 3-phenoxypyridine to treat addiction. U.S. Pat. Nos. 5,039,680 and 5,198,459 to Imperato et al. disclose using a serotonin antagonist to treat chemical addiction. U.S. Pat. No. 5,556,837 to Nestler et. al. discloses infusing BDNF or NT-4 growth factors to inhibit or reverse neurological adaptive changes that correlate with behavioral changes in an addicted individual. U.S. Pat. No. 5,762,925 to Sagan discloses implanting encapsulated adrenal medullary cells into an animal's central nervous system to inhibit the development of opioid intolerance. U.S. Pat. No. 6,204,284 to Beer et al. discloses racemic ()-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in the prevention or relief of a withdrawal syndrome resulting from addiction to drugs and for the treatment of chemical dependencies.

Without treatment, Parkinson's disease progresses to a rigid akinetic state in which patients are incapable of caring for themselves. Death frequently results from complications of immobility, including aspiration pneumonia or pulmonary embolism. Drugs commonly used for the treatment of Parkinson's disease include carbidopa/levodopa, pergolide, bromocriptine, selegiline, amantadine, and trihexyphenidyl hydrochloride. There remains, however, a need for drugs useful for the treatment of Parkinson's disease and having an improved therapeutic profile.

Currently, benzodiazepines are the most commonly used anti-anxiety agents for generalized anxiety disorder. Benzodiazepines, however, carry the risk of producing impairment of cognition and skilled motor functions, particularly in the elderly, which can result in confusion, delerium, and falls with fractures. Sedatives are also commonly prescribed for treating anxiety. The azapirones, such as buspirone, are also used to treat moderate anxiety. The azapirones, however, are less useful for treating severe anxiety accompanied with panic attacks.

Examples of drugs for treating a seizure and epilepsy include carbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproic acid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however, can have side effects such as drowsiness; hyperactivity; hallucinations; inability to concentrate; central and peripheral nervous system toxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingival hyperplasia; gastrointestinal disturbances such as nausea, vomiting, epigastric pain, and anorexia; endocrine effects such as inhibition of antidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; and hypersensitivity such as scarlatiniform rash, morbilliform rash, Stevens-Johnson syndrome, systemic lupus erythematosus, and hepatic necrosis; and hematological reactions such as red-cell aplasia, agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblastic anemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed., 1997).

Symptoms of strokes vary depending on what part of the brain is affected. Symptoms include loss or abnormal sensations in an arm or leg or one side of the body, weakness or paralysis of an arm or leg or one side of the body, partial loss of vison or hearing, double vision, dizziness, slurred speech, difficulty in thinking of the appropriate word or saying it, inability to recognize parts of the body, unusual movements, loss of bladder control, imbalance, and falling, and fainting. The symptoms can be permanent and can be associated with coma or stupor. Examples of drugs for treating strokes include anticoagulants such as heparin, drugs that break up clots such as streptokinase or tissue plasminogen activator, and drugs that reduce swelling such as mannitol or corticosteroids. The Merck Manual of Medical Information 352-355 (R. Berkow ed., 1997).

Pruritus is an unpleasant sensation that prompts scratching. Conventionally, pruritus is treated by phototherapy with ultraviolet B or PUVA or with therapeutic agents such as naltrexone, nalmefene, danazol, tricyclics, and antidepressants.

Selective antagonists of the metabotropic glutamate receptor 5 (“mGluR5”) have been shown to exert analgesic activity in in vivo animal models (K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrul et al., Neuroscience Letters, 292(2):115-118 (2000)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anxiolytic and anti-depressant activity in in vivo animal models (E. Tatarczynska et al., Br. J. Pharmacol. 132(7):1423-1430 (2001) and P. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anti-Parkinson activity in vivo (K. J. Ossowska et al., Neuropharmacology 41(4):413-20 (2001) and P. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown to exert anti-dependence activity in vivo (C. Chiamulera et al., Nature Neuroscience 4(9):873-74 (2001)).

International publication no. WO 01/027107 describes a class of heterocyclic compounds that are sodium/proton exchange inhibitors.

International publication no. WO 99/37304 describes substituted oxoazaheterocycly compounds useful for inhibiting factor Xa.

U.S. Pat. No. 6,248,756 to Anthony et al. and international publication no. WO 97/38665 describe a class of piperidine-containing compounds that inhibit farnesyl-protein transferase (Ftase).

International publication no. WO 98/31669 describes a class of aromatic amines derived from cyclic amines useful as antidepressant drugs.

International publication no. WO 97/28140 describes a class of piperidines derived from 1-(piperazin-1-yl)aryl(oxy/amino)carbonyl-4-aryl-piperidine that are useful as 5-HT1Db receptor antagonists.

International publication no. WO 97/38665 describes a class of piperidine containing compounds that are useful as inhibitors of farnesyl-protein transferase.

U.S. Pat. No. 4,797,419 to Moos et al. describes a class of urea compounds for stimulating the release of acetylcholine and useful for treating symptoms of senile cognitive decline, characterized by decreased cerebral acetylcholine production or release.

U.S. Pat. No. 5,891,889 describes a class of substituted piperidine compounds that are useful as inhibitors of farnesyl-protein transferase, and the farnesylation of the oncogene protein Ras.

There remains, however, a clear need in the art for new drugs useful for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression.

Citation of any reference in Section 2 of this application is not to be construed as an admission that such reference is prior art to the present application.

3. SUMMARY OF THE INVENTION

The present invention encompasses compounds of formula (I):


and pharmaceutically acceptable salts thereof, where

Ar1 is

X is O, S, N—CN, N—OH, or N—OR10;

R1 is —H, -halo, —CH3, —NO2, —CN, —OH, —OCH3, —NH2, C(halo)3, —CH(halo)2, or —CH2(halo);

each R2 is independently:

(a) -halo, —OH, —CN, —NO2, or —NH2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

each R3 is independently:

(a) -halo, —CN, —OH, —NO2, or —NH2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

R4 is —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —OR10, —SR13, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —CON(R13)2, —SO2R10, or —NO2;

each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;

each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or CH2(halo);

R8 and R9 are each independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

R10 is —(C1-C4)alkyl;

each R13 is independently:

(a) —H, or —(C1-C4)alkyl; or

(b) -phenyl or -(3- to 5-membered)heteroaryl each of which is unsubstituted or substituted with one or more R6 groups;

each R14 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each halo is independently —F, —Cl, —Br, or —I;

n is an integer ranging from 0 to 3;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 4; and

m is 0 or 1.

The invention further encompasses compounds of formula (II):


and pharmaceutically acceptable salts thereof, where

Ar3 is

X is O, S, N—CN, N—OH, or N—OR10;

R1 is -halo, —CH3, —NO2, —CN, —OH, —OCH3, —NH2, C(halo)3, —CH(halo)2, or —CH2(halo);

each R2 is independently:

(a) -halo, —OH, or —NH2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

each R3 is independently:

(a) -halo, —CN, —OH, —NO2, or —NH2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

R4 is —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —OR10, —SR13, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —CON(R13)2, —SO2R10, or —NO2;

each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;

each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or CH2(halo);

each R9 is —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

R10 is —(C1-C4)alkyl;

each R11 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;

each R13 is independently:

(a) —H or —(C1-C4)alkyl; or

(b) -phenyl or -(3- to 5-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

each halo is independently —F, —Cl, —Br, or —I;

n is an integer ranging from 0 to 3;

r is an integer ranging from 0 to 6;

s is an integer ranging from 0 to 5; and

m is 0 or 1.

The invention further encompasses compounds of formula (III):


and pharmaceutically acceptable salts thereof, where

Ar1 is

Ar3 is

X is O, S, N—CN, N—OH, or N—OR10;

R1 is —H, -halo, —CH3, —NO2, —CN, —OH, —OCH3, —NH2, C(halo)3, —CH(halo)2, or —CH2(halo);

each R2 is independently:

(a) -halo, —OH, —CN, —NO2, or —NH2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C4)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C9-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

each R3 is independently:

(a) -halo, —CN, —OH, —NO2, or —NH2;

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or

(c) -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

R4 is —OH, —OCF3, -halo, —(C1-C6)alkyl, —CH2OH, —CH2Cl, —CH2Br, —CH2I, —CH2F, —CH(halo)2, —CF3, —OR10, —SR13, —COOH, —COOR10, —C(O)R10, —C(O)H, —OC(O)R10, —OC(O)NHR10, —NHC(O)R13, —CON(R13)2, —SO2R10, or —NO2;

each R5 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;

each R6 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

each R7 is independently —H, —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo)3, —CH(halo)2, or CH2(halo);

each R9 is independently —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C2-C6)alkynyl, —(C3-C8)cycloalkyl, —(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —CH2C(halo)3, —C(halo)3, —CH(halo)2, —CH2(halo), —CN, —OH, -halo, —N3, —NO2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, —OC(O)OR7, —SR7, —S(O)R7, or —S(O)2R7;

R10 is —(C1-C4)alkyl;

each R11 is independently —CN, —OH, —(C1-C6)alkyl, —(C2-C6)alkenyl, -halo, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —OR7, —COR7, —C(O)OR7, —OC(O)R7, or —OC(O)OR7;

each R13 is independently:

(a) —H or —(C1-C4)alkyl; or

(b) -phenyl or -(3- to 5-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;

each halo is independently —F, —Cl, —Br, or —I;

p is an integer ranging from 0 to 2;

r is an integer ranging from 0-6;

s is an integer ranging from 0-5; and

m is 0 or 1.

A compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof (a “Piperidine Compound”), is useful for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington's chorea, ALS, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression (each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effective amount of a Piperidine Compound and a pharmaceutically acceptable carrier or excipient. The compositions are useful for treating or preventing a Condition in an animal.

The invention further relates to methods for treating a Condition comprising administering to an animal in need thereof an effective amount of a Piperidine Compound.

The invention further relates to methods for preventing a Condition comprising administering to an animal in need thereof an effective amount of a Piperidine Compound.

The invention still further relates to methods for inhibiting Vanilloid Receptor 1 (“VR1”) function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of a Piperidine Compound.

The invention still further relates to methods for inhibiting mGluR5 function in a cell, comprising contacting a cell capable of expressing mGluR5 with an effective amount of a Piperidine Compound.

The invention still further relates to methods for inhibiting metabotropic glutamate receptor 1 (“mGluR1”) function in a cell, comprising contacting a cell capable of expressing mGluR1 with an effective amount of a Piperidine Compound.

The invention still further relates to a method for preparing a composition comprising the step of admixing a Piperidine Compound and a pharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a container containing an effective amount of a Piperidine Compound.

The present invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 Piperidine Compounds of Formula (I)

As stated above, the present invention encompasses compounds of Formula (I)


and pharmaceutically acceptable salts thereof, where Ar1, Ar2, R3, R4, X, and m are defined above for the Piperidine Compounds of formula (I).

In one embodiment, Ar1 is a pyridyl group.

In another embodiment, Ar1 is a pyrimidyl group

In another embodiment, Ar1 is a pyrazinyl group.

In another embodiment, Ar1 is a pyridazinyl group.

In another embodiment, Ar1 is a thiazanyl group.

In another embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR10.

In another embodiment, Ar2 is a benzoimidazolyl group.

In another embodiment, Ar2 is a benzothiazolyl group.

In another embodiment, Ar2 is a benzooxazolyl group.

In another embodiment, Ar2 is

In another embodiment, Ar2 is

In another embodiment, n or p is 0.

In another embodiment, n or p is 1.

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, R1 is —H.

In another embodiment, R1 is -halo.

In another embodiment, R1 is —CH3.

In another embodiment, R1 is —NO2.

In another embodiment, R1 is —CN.

In another embodiment, R1 is —OH.

In another embodiment, R1 is —OCH3.

In another embodiment, R1 is —NH2.

In another embodiment, R1 is —C(halo)3.

In another embodiment, R1 is —CH(halo)2.

In another embodiment, R1 is —CH2(halo).

In another embodiment, n or p is 1 and R2 is -halo, —CN, —OH, —NO2, or —NH2.

In another embodiment, n or p is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C4)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C4)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, n or p is 1 and R2 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is -halo, —CN, —OH, —NO2, or —NH2;

In another embodiment, m is 1 and R3 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is —CH3.

In another embodiment, R4 is —OH.

In another embodiment, R4 is —OCF3

In another embodiment, R4 is -halo.

In another embodiment, R4 is —(C1-C6)alkyl.

In another embodiment, R4 is —CH3.

In another embodiment, R4 is —CH2OH.

In another embodiment, R4 is —CH2Cl.

In another embodiment, R4 is —CH2Br.

In another embodiment, R4 is —CH2I.

In another embodiment, R4 is —CH2F.

In another embodiment, R4 is —CH(halo)2.

In another embodiment, R4 is —CF3.

In another embodiment, R4 is —NO2.

In another embodiment, R4 is —OR10.

In another embodiment, R4 is —SR13.

In another embodiment, R4 is —C(O)R10.

In another embodiment, R4 is —COOH.

In another embodiment, R4 is —C(O)H.

In another embodiment, R4 is —COOR10.

In another embodiment, R4 is —OC(O)R10.

In another embodiment, R4 is —SO2R10.

In another embodiment, R4 is —OC(O)NHR10.

In another embodiment, R4 is —NHC(O)R13.

In another embodiment, 4 is —CON(R13)2.

In another embodiment, Ar2 is a benzothiazolyl, benzoimidazolyl, or benzooxazolyl group; and at least one of R8 and R9 is —H.

In another embodiment, Ar2 is


and q is 1.

In another embodiment, Ar2 is


and q is 1.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is -halo, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —F, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Cl, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Br, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —I, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is -halo, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —F, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Cl, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Br, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —I, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is -halo, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —F, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Cl, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Br, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —I, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is -halo, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —F, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Cl, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Br, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —I, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is -halo, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —F, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Cl, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —Br, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —I, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OH, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OH, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OH, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OH, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OH, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OR10, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OR10, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OR10 and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OR10, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —OR10, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is a benzooxazozolyl group.

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is

In another embodiment, Ar1 is a pyridyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is -halo, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —F, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Cl, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Br, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —I, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is -halo, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —F, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Cl, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Br, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —I, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is -halo, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —F, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Cl, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Br, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —I, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is -halo, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —F, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Cl, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Br, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —I, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is -halo, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —F, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Cl, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —Br, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —I, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OH, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OH, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OH, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OH, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OH, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —CH3, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —CH3, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —CH3, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —CH3, and Ar2 is a cyclohexyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —CH3, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OR10, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OR10, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OR10, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OR10, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —OR10, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is a benzothiazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is a benzoimidazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is a benzooxazolyl group.

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is

In another embodiment, Ar1 is a pyridazinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar2 is

The invention also relates compounds of formula (I), and pharmaceutically acceptable salts thereof, where:

Ar2 is

each R3 is independently:

(a) -halo, —CN, —OH, —NO2, or —NH2; or

(b) —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, each of which is unsubstituted or substituted with one or more R5 groups; and

at least one of R8 or R9 is other than —H.

4.2 Piperidine Compounds of Formula (II)

This invention also relates to compounds of formula (II):


and pharmaceutically acceptable salts thereof, where R1, R2, Ar3, R3, R4, X, n and m are defined above for the Piperidine Compounds of formula (II).

In one embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR10.

In another embodiment, Ar3 is

In another embodiment, Ar3 is

It is to be understood that when two R11 groups are present on the same carbon atom, the two R11 groups on the same carbon atom are not both —CN, —OH, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —COR7, —OC(O)R7, or —OC(O)OR7.

In another embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, R1 is -halo.

In another embodiment, R1 is —CH3.

In another embodiment, R1 is —NO2.

In another embodiment, R1 is —CN.

In another embodiment, R1 is —OH.

In another embodiment, R1 is —OCH3.

In another embodiment, R1 is —NH2.

In another embodiment, R1 is —C(halo)3.

In another embodiment, R1 is —CH(halo)2.

In another embodiment, R1 is —CH2(halo).

In another embodiment, n is 1 and R2 is -halo, —OH, or —NH2.

In another embodiment, n is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, n is 1 and R2 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is -halo, —CN, —OH, —NO2, or —NH2;

In another embodiment, m is 1 and R3 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is —CH3.

In another embodiment, R4 is —OH.

In another embodiment, R4 is —OCF3

In another embodiment, R4 is -halo.

In another embodiment, R4 is —(C1-C6)alkyl.

In another embodiment, R4 is —CH3.

In another embodiment, R4 is —CH2OH.

In another embodiment, R4 is —CH2Cl.

In another embodiment, R4 is —CH2Br.

In another embodiment, R4 is —CH2I.

In another embodiment, R4 is —CH2F.

In another embodiment, R4 is —CH(halo)2.

In another embodiment, R4 is —CF3.

In another embodiment, R4 is —NO2.

In another embodiment, R4 is —OR10.

In another embodiment, R4 is —SR13.

In another embodiment, R4 is —C(O)R10.

In another embodiment, R4 is —COOH.

In another embodiment, R4 is —C(O)H.

In another embodiment, R4 is —COOR10.

In another embodiment, R4 is —C(O)OR10.

In another embodiment, R4 is —SO2R10.

In another embodiment, R4 is —OC(O)NHR10.

In another embodiment, R4 is —NHC(O)R13.

In another embodiment, R4 is —CON(R13)2.

In another embodiment, Ar3 is


and s is 1.

In another embodiment, Ar3 is


and r is 1.

In another embodiment, X is O, m is 0, R4 is -halo, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —F, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —Cl, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —Br, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —I, and Ar3 is

In another embodiment, X is O, m is 0, R4 is -halo, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —F, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —Cl, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —Br, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —I, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —OH, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —OH, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —OH, and Ar3 is


s is 1; and R9 is —(C1-C6)alkyl.

In another embodiment, X is O, m is 0, R4 is —OH, and Ar3 is


s is 1; and R9 is —CH3.

In another embodiment, X is O, m is 0, R4 is —CH3, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —CH3, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —CH3, and Ar3 is


s is 1, and R9 is —(C1-C6)alkyl.

In another embodiment, X is O, m is 0, R4 is —CH3, and Ar3 is


s is 1, and R9 is —CH3.

In another embodiment, X is O, m is 0, R4 is —OR10, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —OR10, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —OR10, and Ar3 is


s is 1, and R9 is —(C1-C6)alkyl.

In another embodiment, X is O, m is 0, R4 is —OR10, and Ar3 is


s is 1, and R9 is —CH3.

In another embodiment, X is O, m is 0, R4 is —C(O)R10, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —C(O)R10, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —C(O)R10, and Ar3 is


s is 1, and R9 is —(C1-C6)alkyl.

In another embodiment, X is O, m is 0, R4 is —C(O)R10, and Ar3 is


s is 1, and R9 is —CH3.

4.3 Piperidine Compounds of Formula (III)

The invention also relates to compounds of formula (III):


and pharmaceutically acceptable salts thereof, where Ar1, Ar3, R3, R4, X and m are defined above for the Piperidine Compounds of formula (III).

In one embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR10.

In another embodiment, Ar1 is a pyrimidyl group.

In another embodiment, Ar1 is a pyrazinyl group.

In another embodiment, Ar1 is a pyridazinyl group.

In another embodiment, Ar1 is a thiazanyl group.

In another embodiment, Ar3 is

In another embodiment, Ar3

It is to be understood that when two R11 groups are present on the same carbon atom, the two R11 groups on the same carbon atom are not both —CN, —OH, —N3, —NO2, —N(R7)2, —CH═NR7, —NR7OH, —COR7, —OC(O)R7, or —OC(O)OR7.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, R1 is —H.

In another embodiment, R1 is -halo.

In another embodiment, R1 is —CH3.

In another embodiment, R1 is —NO2.

In another embodiment, R1 is —CN.

In another embodiment, R1 is —OH.

In another embodiment, R1 is —OCH3.

In another embodiment, R1 is —NH2.

In another embodiment, R1 is —C(halo)3.

In another embodiment, R1 is —CH(halo)2.

In another embodiment, R1 is —CH2(halo).

In another embodiment, p is 1 and R2 is -halo, —CN, —OH, —NO2, or —NH2.

In another embodiment, p is 1 and R2 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C4)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, p is 1 and R2 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is -halo, —CN, —OH, —NO2, or —NH2;

In another embodiment, m is 1 and R3 is —(C1-C10)alkyl, —(C2-C10)alkenyl, —(C2-C10)alkynyl, —(C3-C10)cycloalkyl, —(C8-C14)bicycloalkyl, —(C8-C14)tricycloalkyl, —(C5-C10)cycloalkenyl, —(C8-C14)bicycloalkenyl, —(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups.

In another embodiment, m is 1 and R3 is -phenyl, -naphthyl, —(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups.

In another embodiment, m is 1 and R3 is —CH3.

In another embodiment, R4 is —OH.

In another embodiment, R4 is —OCF3

In another embodiment, R4 is -halo.

In another embodiment, R4 is —(C1-C6)alkyl.

In another embodiment, R4 is —CH3.

In another embodiment, R4 is —CH2OH.

In another embodiment, R4 is —CH2Cl.

In another embodiment, R4 is —CH2Br.

In another embodiment, R4 is —CH2I.

In another embodiment, R4 is —CH2F.

In another embodiment, R4 is —CH(halo)2.

In another embodiment, R4 is —CF3.

In another embodiment, R4 is —NO2.

In another embodiment, R4 is —OR10.

In another embodiment, R4 is —SR13.

In another embodiment, R4 is —C(O)R10.

In another embodiment, R4 is —COOH.

In another embodiment, R4 is —C(O)H.

In another embodiment, R4 is —COOR10.

In another embodiment, R4 is —OC(O)R10.

In another embodiment, R4 is —SO2R10.

In another embodiment, R4 is —OC(O)NHR10.

In another embodiment, R4 is —NHC(O)R13.

In another embodiment, R4 is —CON(R13)2.

In another embodiment, Ar3 is


and s is 1.

In another embodiment, Ar3 is


and r is 1.

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is -halo, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —F, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —Cl, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —Br, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —I, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is -halo, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —F, and Ar3 is

In another embodiment, X is O, m is 0, R4 is —Cl, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —Br, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —I, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —OH, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —OH, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —OH, and Ar3 is


where s is 1, and R9 is —(C1-C6)alkyl.

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —OH, and Ar3 is


where s is 1, and R9 is —CH3.

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —CH3, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —CH3, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —CH3, and Ar3 is


and s is 1, and R9 is —(C1-C6)alkyl.

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —CH3, and Ar3 is


where s is 1, and R9 is —CH3.

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —OR10, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —OR10, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —OR10, and Ar3 is


s is 1, and R9 is —(C1-C6)alkyl.

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —OR10, and Ar3 is


s is 1, and R9 is —CH3.

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar3 is

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar3 is


s is 1, and R9 is —(C1-C6)alkyl.

In another embodiment, Ar1 is a pyradizinyl group, X is O, m is 0, R4 is —C(O)R10, and Ar3 is


s is 1, and R9 is —CH3.

4.4 Piperidine Compounds of Formulas (I)-(III)

In the Piperidine Compounds that have an R3 group, the R3 group can be attached to a carbon atom adjacent to the carbon atom attached to the R4 group, or the R3 group can be attached to a carbon atom adjacent to the nitrogen atom attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group. In one embodiment, the R3 group is attached to a carbon atom adjacent to the carbon atom attached to the R4 group. In another embodiment, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached —C(X)NH—Ar2 or —C(X)NH—Ar3 group.

In one embodiment, where the Piperidine Compound has an R3 group, the carbon atom to which the R3 group is attached has the (R) configuration. In another embodiment, where the Piperidine Compound has an R3 group, the carbon atom to which the R3 group is attached has the (S) configuration.

In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon atom attached to the R4 group, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon attached to the R4 group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon attached to the R4 group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH3. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon attached to the R4 group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CF3. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon attached to the R4 group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH2CH3.

In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH3. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CF3. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (R) configuration, and R3 is —CH2CH3.

In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon atom attached to the R4 group, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon attached to the R4 group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon attached to the R4 group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH3. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon attached to the R4 group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CF3. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the carbon attached to the R4 group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH2CH3.

In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen atom attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, and the carbon to which the R3 group is attached is in the (S) configuration. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —(C1-C4)alkyl unsubstituted or substituted with one or more halo groups. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 group or —C(X)NH—Ar3, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH3. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CF3. In another embodiment, the Piperidine Compound has an R3 group, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (S) configuration, and R3 is —CH2CH3.

In another embodiment, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, and the R3 group is a —CH3. In another embodiment, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, and the R3 group is a —CF3. In another embodiment, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, and the R3 group is a —CH2CH3. In another embodiment, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, and the carbon to which the R3 group is attached is in the (R) configuration. In another embodiment, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (R) configuration, and the R3 group is a —CH3. In another embodiment, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (R) configuration, and the R3 group is a —CF3. In another embodiment, the R3 group is attached to a carbon atom adjacent to the nitrogen attached to the —C(X)NH—Ar2 or —C(X)NH—Ar3 group, the carbon to which the R3 group is attached is in the (R) configuration, and the R3 group is a —CH2CH3.

In another embodiment, m is 1 and R3 is cis to R4.

In another embodiment, m is 1 and R3 is trans to R4.

Illustrative Piperidine Compounds are listed below in Tables 1-18:

TABLE 1
(IIa)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
AAA —Cl —H
AAB —Cl -tert-butyl
AAC —Cl -iso-butyl
AAD —Cl -sec-butyl
AAE —Cl -cyclohexyl
AAF —Cl -tert-butoxy
AAG —Cl -iso-propoxy
AAH —Cl —CF3
AAI —Cl —CH2CF3
AAJ —Cl —OCF3
AAK —Cl —Cl
AAL —Cl —Br
AAM —Cl —I
AAN —Cl -n-butyl
AAO —Cl -n-propyl
AAP —F —H
AAQ —F -tert-butyl
AAR —F -iso-butyl
AAS —F -sec-butyl
AAT —F -cyclohexyl
AAU —F -tert-butoxy
AAV —F -iso-propoxy
AAW —F —CF3
AAX —F —CH2CF3
AAY —F —OCF3
AAZ —F —Cl
ABA —F —Br
ABB —F —I
ABC —F -n-butyl
ABD —F -n-propyl
ABE —CH3 —H
ABF —CH3 -iso-butyl
ABG —CH3 -tert-butyl
ABH —CH3 -sec-butyl
ABI —CH3 -cyclohexyl
ABJ —CH3 -tert-butoxy
ABK —CH3 -iso-propoxy
ABL —CH3 —CF3
ABM —CH3 —CH2CF3
ABN —CH3 —OCF3
ABO —CH3 —Cl
ABP —CH3 —Br
ABQ —CH3 —I
ABR —CH3 -n-butyl
ABS —CH3 -n-propyl
ABT —CF3 —H
ABU —CF3 -tert-butyl
ABV —CF3 -iso-butyl
ABW —CF3 -sec-butyl
ABX —CF3 -cyclohexyl
ABY —CF3 -tert-butoxy
ABZ —CF3 -iso-propoxy
ACA —CF3 —CF3
ACB —CF3 —CH2CF3
ACC —CF3 —OCF3
ACD —CF3 —Cl
ACE —CF3 —Br
ACF —CF3 —I
ACG —CF3 -n-butyl
ACH —CF3 -n-propyl
ACI —CHF2 -tert-butyl
ACJ —CHF2 —H
ACK —CHF2 -iso-butyl
ACL —CHF2 -sec-butyl
ACM —CHF2 -cyclohexyl
CAN —CHF2 -tert-butoxy
ACO —CHF2 -iso-propoxy
ACP —CHF2 —CF3
ACQ —CHF2 —CH2CF3
ACR —CHF2 —OCF3
ACS —CHF2 —Cl
ACT —CHF2 —Br
ACU —CHF2 —I
ACV —CHF2 -n-butyl
ACW —CHF2 -n-propyl
ACX —OH —H
ACY —OH -tert-butyl
ACZ —OH -iso-butyl
ADA —OH -sec-butyl
ADB —OH -cyclohexyl
ADC —OH -tert-butoxy
ADD —OH -iso-propoxy
ADE —OH —CF3
ADF —OH —CH2CF3
ADG —OH —OCF3
ADH —OH —Cl
ADI —OH —Br
ADJ —OH —I
ADK —OH -n-butyl
ADL —OH -n-propyl
ADM —NO2 —H
AND —NO2 -tert-butyl
ADO —NO2 -iso-butyl
ADP —NO2 -sec-butyl
ADQ —NO2 -cyclohexyl
ADR —NO2 -tert-butoxy
ADS —NO2 -iso-propoxy
ADT —NO2 —CF3
ADU —NO2 —CH2CF3
ADV —NO2 —OCF3
ADW —NO2 —Cl
ADX —NO2 —Br
ADY —NO2 —I
ADZ —NO2 -n-butyl
AEA —NO2 -n-propyl
AEB —CN —H
AEC —CN -tert-butyl
AED —CN -iso-butyl
AEE —CN -sec-butyl
AEF —CN -cyclohexyl
AEG —CN -tert-butoxy
AEH —CN -iso-propoxy
AEI —CN —CF3
AEJ —CN —CH2CF3
AEK —CN —OCF3
AEL —CN —Cl
AEM —CN —Br
AEN —CN —I
AEO —CN -n-butyl
AEP —CN -n-propyl
AEQ —Br —H
AER —Br -tert-butyl
AES —Br -iso-butyl
AET —Br -sec-butyl
AEU —Br -cyclohexyl
AEV —Br -tert-butoxy
AEW —Br -iso-propoxy
AEX —Br —CF3
AEY —Br —CH2CF3
AEZ —Br —OCF3
AFA —Br —Cl
AFB —Br —Br
AFC —Br —I
AFD —Br -n-butyl
AFE —Br -n-propyl
AFF —I -tert-butyl
AFG —I —H
AFH —I -iso-butyl
AFI —I -sec-butyl
AFJ —I -cyclohexyl
AFK —I -tert-butoxy
AFL —I -iso-propoxy
AFM —I —CF3
AFN —I —CH2CF3
AFO —I —OCF3
AFP —I —Cl
AFQ —I —Br
AFR —I —I
AFS —I -n-butyl
AFT —I -n-propyl

TABLE 2
(IIb)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
AFU —Cl —H
AFV —Cl -tert-butyl
AFW —Cl -iso-butyl
AFX —Cl -sec-butyl
AFY —Cl -cyclohexyl
AFZ —Cl -tert-butoxy
AGA —Cl -iso-propoxy
AGB —Cl —CF3
AGC —Cl —CH2CF3
AGD —Cl —OCF3
AGE —Cl —Cl
AGF —Cl —Br
AGG —Cl —I
AGH —Cl -n-butyl
AGI —Cl -n-propyl
AGJ —F —H
AGK —F -tert-butyl
AGL —F -iso-butyl
AGM —F -sec-butyl
AGN —F -cyclohexyl
AGO —F -tert-butoxy
AGP —F -iso-propoxy
AGQ —F —CF3
AGR —F —CH2CF3
AGS —F —OCF3
AGT —F —Cl
AGU —F —Br
AGV —F —I
AGW —F -n-butyl
AGX —F -n-propyl
AGY —CH3 —H
AGZ —CH3 -tert-butyl
AHA —CH3 -iso-butyl
AHB —CH3 -sec-butyl
AHC —CH3 -cyclohexyl
AHD —CH3 -tert-butoxy
AHE —CH3 -iso-propoxy
AHF —CH3 —CF3
AHG —CH3 —CH2CF3
AHH —CH3 —OCF3
AHI —CH3 —Cl
AHJ —CH3 —Br
AHK —CH3 —I
AHL —CH3 -n-butyl
AHM —CH3 -n-propyl
AHN —CF3 —H
AHO —CF3 -tert-butyl
AHP —CF3 -iso-butyl
AHQ —CF3 -sec-butyl
AHR —CF3 -cyclohexyl
AHS —CF3 -tert-butoxy
AHT —CF3 -iso-propoxy
AHU —CF3 —CF3
AHV —CF3 —CH2CF3
AHW —CF3 —OCF3
AHX —CF3 —Cl
AHY —CF3 —Br
AHZ —CF3 —I
AIA —CF3 -n-butyl
AIB —CF3 -n-propyl
AIC —CHF2 -tert-butyl
AID —CHF2 —H
AIE —CHF2 -iso-butyl
AIF —CHF2 -sec-butyl
AIG —CHF2 -cyclohexyl
AIH —CHF2 -tert-butoxy
AII —CHF2 -iso-propoxy
AIJ —CHF2 —CF3
AIK —CHF2 —CH2CF3
AIL —CHF2 —OCF3
AIM —CHF2 —Cl
AIN —CHF2 —Br
AIO —CHF2 —I
AIP —CHF2 -n-butyl
AIQ —CHF2 -n-propyl
AIR —OH —H
AIS —OH -tert-butyl
AIT —OH -iso-butyl
AIU —OH -sec-butyl
AIV —OH -cyclohexyl
AIW —OH -tert-butoxy
AIX —OH -iso-propoxy
AIY —OH —CF3
AIZ —OH —CH2CF3
AJA —OH —OCF3
AJB —OH —Cl
AJC —OH —Br
AJD —OH —I
AJE —OH -n-butyl
AJF —OH -n-propyl
AJG —NO2 —H
AJH —NO2 -tert-butyl
AJI —NO2 -iso-butyl
AJJ —NO2 -sec-butyl
AJK —NO2 -cyclohexyl
AJL —NO2 -tert-butoxy
AJM —NO2 -iso-propoxy
AJN —NO2 —CF3
AJO —NO2 —CH2CF3
AJP —NO2 —OCF3
AJQ —NO2 —Cl
AJR —NO2 —Br
AJS —NO2 —I
AJT —NO2 -n-butyl
AJU —NO2 -n-propyl
AJV —CN —H
AJW —CN -tert-butyl
AJX —CN -iso-butyl
AJY —CN -sec-butyl
AJZ —CN -cyclohexyl
AKA —CN -tert-butoxy
AKB —CN -iso-propoxy
AKC —CN —CF3
AKD —CN —CH2CF3
AKE —CN —OCF3
AKF —CN —Cl
AKG —CN —Br
AKH —CN —I
AKI —CN -n-butyl
AKJ —CN -n-propyl
AKK —Br —H
AKL —Br -tert-butyl
AKM —Br -iso-butyl
AKN —Br -sec-butyl
AKO —Br -cyclohexyl
AKP —Br -tert-butoxy
AKQ —Br -iso-propoxy
AKR —Br —CF3
AKS —Br —CH2CF3
AKT —Br —OCF3
AKU —Br —Cl
AKV —Br —Br
AKW —Br —I
AKX —Br -n-butyl
AKY —Br -n-propyl
AKZ —I -tert-butyl
ALA —I —H
ALB —I -iso-butyl
ALC —I -sec-butyl
ALD —I -cyclohexyl
ALE —I -tert-butoxy
ALF —I -iso-propoxy
ALG —I —CF3
ALH —I —CH2CF3
ALI —I —OCF3
ALJ —I —Cl
ALK —I —Br
ALL —I —I
ALM —I -n-butyl
ALN —I -n-propyl

TABLE 3
(IIc)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
ALO —Cl —H
ALP —Cl -tert-butyl
ALQ —Cl -iso-butyl
ALR —Cl -sec-butyl
ALS —Cl -cyclohexyl
ALT —Cl -tert-butoxy
ALU —Cl -iso-propoxy
ALV —Cl —CF3
ALW —Cl —CH2CF3
ALX —Cl —OCF3
ALY —Cl —Cl
ALZ —Cl —Br
AMA —Cl —I
AMB —Cl -n-butyl
AMC —Cl -n-propyl
AMD —F —H
AME —F -tert-butyl
AMF —F -iso-butyl
AMG —F -sec-butyl
AMH —F -cyclohexyl
AMI —F -tert-butoxy
AMJ —F -iso-propoxy
AMK —F —CF3
AML —F —CH2CF3
AMM —F —OCF3
AMN —F —Cl
AMO —F —Br
AMP —F —I
AMQ —F -n-butyl
AMR —F -n-propyl
AMS —CH3 —I
AMT —CH3 -tert-butyl
AMU —CH3 -iso-butyl
AMV —CH3 -sec-butyl
AMW —CH3 -cyclohexyl
AMX —CH3 -tert-butoxy
AMY —CH3 -iso-propoxy
AMZ —CH3 —CF3
ANA —CH3 —CH2CF3
ANB —CH3 —OCF3
ANC —CH3 —Cl
AND —CH3 —Br
ANE —CH3 —I
ANF —CH3 -n-butyl
ANG —CH3 -n-propyl
ANH —CF3 —H
ANI —CF3 -tert-butyl
ANJ —CF3 -iso-butyl
ANK —CF3 -sec-butyl
ANL —CF3 -cyclohexyl
ANM —CF3 -tert-butoxy
ANN —CF3 -iso-propoxy
ANO —CF3 —CF3
ANP —CF3 —CH2CF3
ANQ —CF3 —OCF3
ANR —CF3 —Cl
ANS —CF3 —Br
ANT —CF3 —I
ANU —CF3 -n-butyl
ANV —CF3 -n-propyl
ANW —CHF2 -tert-butyl
ANX —CHF2 —H
ANY —CHF2 -iso-butyl
ANZ —CHF2 -sec-butyl
AOA —CHF2 -cyclohexyl
AOB —CHF2 -tert-butoxy
AOC —CHF2 -iso-propoxy
AOD —CHF2 —CF3
AOE —CHF2 —CH2CF3
AOF —CHF2 —OCF3
AOG —CHF2 —Cl
AOH —CHF2 —Br
AOI —CHF2 —I
AOJ —CHF2 -n-butyl
AOK —CHF2 -n-propyl
AOL —OH —H
AOM —OH -tert-butyl
AON —OH -iso-butyl
AOO —OH -sec-butyl
AOP —OH -cyclohexyl
AOQ —OH -tert-butoxy
AOR —OH -iso-propoxy
AOS —OH —CF3
AOT —OH —CH2CF3
AOU —OH —OCF3
AOV —OH —Cl
AOW —OH —Br
AOX —OH —I
AOY —OH -n-butyl
AOZ —OH -n-propyl
APA —NO2 —H
APB —NO2 -tert-butyl
APC —NO2 -iso-butyl
APD —NO2 -sec-butyl
APE —NO2 -cyclohexyl
APF —NO2 -tert-butoxy
APG —NO2 -iso-propoxy
APH —NO2 —CF3
API —NO2 —CH2CF3
APJ —NO2 —OCF3
APK —NO2 —Cl
APL —NO2 —Br
APM —NO2 —I
APN —NO2 -n-butyl
APO —NO2 -n-propyl
APP —CN —H
APQ —CN -tert-butyl
APR —CN -iso-butyl
APS —CN -sec-butyl
APT —CN -cyclohexyl
APU —CN -tert-butoxy
APV —CN -iso-propoxy
APW —CN —CF3
APX —CN —CH2CF3
APY —CN —OCF3
APZ —CN —Cl
AQA —CN —Br
AQB —CN —I
AQC —CN -n-butyl
AQD —CN -n-propyl
AQE —Br —H
AQF —Br -tert-butyl
AQG —Br -iso-butyl
AQH —Br -sec-butyl
AQI —Br -cyclohexyl
AQJ —Br -tert-butoxy
AQK —Br -iso-propoxy
AQL —Br —CF3
AQM —Br —CH2CF3
AQN —Br —OCF3
AQO —Br —Cl
AQP —Br —Br
AQQ —Br —I
AQR —Br -n-butyl
AQS —Br -n-propyl
AQT —I -tert-butyl
AQU —I —H
AQV —I -iso-butyl
AQW —I -sec-butyl
AQX —I -cyclohexyl
AQY —I -tert-butoxy
AQZ —I -iso-propoxy
ARA —I —CF3
ARB —I —CH2CF3
ARC —I —OCF3
ARD —I —Cl
ARE —I —Br
ARF —I —I
ARG —I -n-butyl
ARH —I -n-propyl

TABLE 4
(IId)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
ARI —Cl —H
ARJ —Cl -tert-butyl
ARK —Cl -iso-butyl
ARL —Cl -sec-butyl
ARM —Cl -cyclohexyl
ARN —Cl -tert-butoxy
ARO —Cl -iso-propoxy
ARP —Cl —CF3
ARQ —Cl —CH2CF3
ARR —Cl —OCF3
ARS —Cl —Cl
ART —Cl —Br
ARU —Cl —I
ARV —Cl -n-butyl
ARW —Cl -n-propyl
ARX —F —H
ARY —F -tert-butyl
ARZ —F -iso-butyl
ASA —F -sec-butyl
ASB —F -cyclohexyl
ASC —F -tert-butoxy
ASD —F -iso-propoxy
ASE —F —CF3
ASF —F —CH2CF3
ASG —F —OCF3
ASH —F —Cl
ASI —F —Br
ASJ —F —I
ASK —F -n-butyl
ASL —F -n-propyl
ASM —CH3 —H
ASN —CH3 -tert-butyl
ASO —CH3 -iso-butyl
ASP —CH3 -sec-butyl
ASQ —CH3 -cyclohexyl
ASR —CH3 -tert-butoxy
ASS —CH3 -iso-propoxy
AST —CH3 —CF3
ASU —CH3 —CH2CF3
ASV —CH3 —OCF3
ASW —CH3 —Cl
ASX —CH3 —Br
ASY —CH3 —I
ASZ —CH3 -n-butyl
ATA —CH3 -n-propyl
ATB —CF3 —H
ATC —CF3 -tert-butyl
ATD —CF3 -iso-butyl
ATE —CF3 -sec-butyl
ATF —CF3 -cyclohexyl
ATG —CF3 -tert-butoxy
ATH —CF3 -iso-propoxy
ATI —CF3 —CF3
ATJ —CF3 —CH2CF3
ATK —CF3 —OCF3
ATL —CF3 —Cl
ATM —CF3 —Br
ATN —CF3 —I
ATO —CF3 -n-butyl
ATP —CF3 -n-propyl
ATQ —CHF2 -tert-butyl
ATR —CHF2 —H
ATS —CHF2 -iso-butyl
ATT —CHF2 -sec-butyl
ATU —CHF2 -cyclohexyl
ATV —CHF2 -tert-butoxy
ATW —CHF2 -iso-propoxy
ATX —CHF2 —CF3
ATY —CHF2 —CH2CF3
ATZ —CHF2 —OCF3
AUA —CHF2 —Cl
AUB —CHF2 —Br
AUC —CHF2 —I
AUD —CHF2 -n-butyl
AUE —CHF2 -n-propyl
AUF —OH —H
AUG —OH -tert-butyl
AUH —OH -iso-butyl
AUI —OH -sec-butyl
AUJ —OH -cyclohexyl
AUK —OH -tert-butoxy
AUL —OH -iso-propoxy
AUM —OH —CF3
AUN —OH —CH2CF3
AUO —OH —OCF3
AUP —OH —Cl
AUQ —OH —Br
AUR —OH —I
AUS —OH -n-butyl
AUT —OH -n-propyl
AUU —NO2 —H
AUV —NO2 -tert-butyl
AUW —NO2 -iso-butyl
AUX —NO2 -sec-butyl
AUY —NO2 -cyclohexyl
AUZ —NO2 -tert-butoxy
AVA —NO2 -iso-propoxy
AVB —NO2 —CF3
AVC —NO2 —CH2CF3
AVD —NO2 —OCF3
AVE —NO2 —Cl
AVF —NO2 —Br
AVG —NO2 —I
AVH —NO2 -n-butyl
AVI —NO2 -n-propyl
AVJ —CN —H
AVK —CN -tert-butyl
AVL —CN -iso-butyl
AVM —CN -sec-butyl
AVN —CN -cyclohexyl
AVO —CN -tert-butoxy
AVP —CN -iso-propoxy
AVQ —CN —CF3
AVR —CN —CH2CF3
AVS —CN —OCF3
AVT —CN —Cl
AVU —CN —Br
AVV —CN —I
AVW —CN -n-butyl
AVX —CN -n-propyl
AVY —Br —H
AVZ —Br -tert-butyl
AWA —Br -iso-butyl
AWB —Br -sec-butyl
AWC —Br -cyclohexyl
AWD —Br -tert-butoxy
AWE —Br -iso-propoxy
AWF —Br —CF3
AWG —Br —CH2CF3
AWH —Br —OCF3
AWI —Br —Cl
AWJ —Br —Br
AWK —Br —I
AWL —Br -n-butyl
AWM —Br -n-propyl
AWN —I -tert-butyl
AWO —I —H
AWP —I -iso-butyl
AWQ —I -sec-butyl
AWR —I -cyclohexyl
AWS —I -tert-butoxy
AWT —I -iso-propoxy
AWU —I —CF3
AWV —I —CH2CF3
AWW —I —OCF3
AWX —I —Cl
AWY —I —Br
AWZ —I —I
AXA —I -n-butyl
AXB —I -n-propyl

TABLE 5
(IIe)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
AXC —Cl —H
AXD —Cl -tert-butyl
AXE —Cl -iso-butyl
AXF —Cl -sec-butyl
AXG —Cl -cyclohexyl
AXH —Cl -tert-butoxy
AXI —Cl -iso-propoxy
AXJ —Cl —CF3
AXK —Cl —CH2CF3
AXL —Cl —OCF3
AXM —Cl —Cl
AXN —Cl —Br
AXO —Cl —I
AXP —Cl -n-butyl
AXQ —Cl -n-propyl
AXR —F —H
AXS —F -tert-butyl
AXT —F -iso-butyl
AXU —F -sec-butyl
AXV —F -cyclohexyl
AXW —F -tert-butoxy
AXX —F -iso-propoxy
AXY —F —CF3
AXZ —F —CH2CF3
AYA —F —OCF3
AYB —F —Cl
AYC —F —Br
AYD —F —I
AYE —F -n-butyl
AYE —F -n-propyl
AYG —CH3 —H
AYH —CH3 -tert-butyl
AYI —CH3 -iso-butyl
AYJ —CH3 -sec-butyl
AYK —CH3 -cyclohexyl
AYL —CH3 -tert-butoxy
AYM —CH3 -iso-propoxy
AYN —CH3 —CF3
AYO —CH3 —CH2CF3
AYP —CH3 —OCF3
AYQ —CH3 —Cl
AYR —CH3 —Br
AYS —CH3 —I
AYT —CH3 -n-butyl
AYU —CH3 -n-propyl
AYV —CF3 —H
AYW —CF3 -tert-butyl
AYX —CF3 -iso-butyl
AYY —CF3 -sec-butyl
AYZ —CF3 -cyclohexyl
AZA —CF3 -tert-butoxy
AZB —CF3 -iso-propoxy
AZC —CF3 —CF3
AZD —CF3 —CH2CF3
AZE —CF3 —OCF3
AZF —CF3 —Cl
AZG —CF3 —Br
AZH —CF3 —I
AZI —CF3 -n-butyl
AZJ —CF3 -n-propyl
AZK —CHF2 -tert-butyl
AZL —CHF2 —H
AZM —CHF2 -iso-butyl
AZN —CHF2 -sec-butyl
AZO —CHF2 -cyclohexyl
AZP —CHF2 -tert-butoxy
AZQ —CHF2 -iso-propoxy
AZR —CHF2 —CF3
AZS —CHF2 —CH2CF3
AZT —CHF2 —OCF3
AZU —CHF2 —Cl
AZV —CHF2 —Br
AZW —CHF2 —I
AZX —CHF2 -n-butyl
AZY —CHF2 -n-propyl
AZZ —OH —H
BAA —OH -tert-butyl
BAB —OH -iso-butyl
BAC —OH -sec-butyl
BAD —OH -cyclohexyl
BAB —OH -tert-butoxy
BAF —OH -iso-propoxy
BAG —OH —CF3
BAH —OH —CH2CF3
BAI —OH —OCF3
BAJ —OH —Cl
BAK —OH —Br
BAL —OH —I
BAM —OH -n-butyl
BAN —OH -n-propyl
BAO —NO2 —H
BAP —NO2 -tert-butyl
BAQ —NO2 -iso-butyl
BAR —NO2 -sec-butyl
BAS —NO2 -cyclohexyl
BAT —NO2 -tert-butoxy
BAU —NO2 -iso-propoxy
BAV —NO2 —CF3
BAW —NO2 —CH2CF3
BAX —NO2 —OCF3
BAY —NO2 —Cl
BAZ —NO2 —Br
BBA —NO2 —I
BBB —NO2 -n-butyl
BBC —NO2 -n-propyl
BBD —CN —H
BBE —CN -tert-butyl
BBF —CN -iso-butyl
BBG —CN -sec-butyl
BBH —CN -cyclohexyl
BBI —CN -tert-butoxy
BBJ —CN -iso-propoxy
BBK —CN —CF3
BBL —CN —CH2CF3
BBM —CN —OCF3
BBN —CN —Cl
BBO —CN —Br
BBP —CN —I
BBQ —CN -n-butyl
BBR —CN -n-propyl
BBS —Br —H
BBT —Br -tert-butyl
BBU —Br -iso-butyl
BBV —Br -sec-butyl
BBW —Br -cyclohexyl
BBX —Br -tert-butoxy
BBY —Br -iso-propoxy
BBZ —Br —CF3
BCA —Br —CH2CF3
BCB —Br —OCF3
BCC —Br —Cl
BCD —Br —Br
BCE —Br —I
BCF —Br -n-butyl
BCG —Br -n-propyl
BCH —I -tert-butyl
BCI —I —H
BCJ —I -iso-butyl
BCK —I -sec-butyl
BCL —I -cyclohexyl
BCM —I -tert-butoxy
BCN —I -iso-propoxy
BCO —I —CF3
BCP —I —CH2CF3
BCQ —I —OCF3
BCR —I —Cl
BCS —I —Br
BCT —I —I
BCU —I -n-butyl
BCV —I -n-propyl

TABLE 6
(IIf)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
BCW —Cl —H
BCX —Cl -tert-butyl
BCY —Cl -iso-butyl
BCZ —Cl -sec-butyl
BDA —Cl -cyclohexyl
BDB —Cl -tert-butoxy
BDC —Cl -iso-propoxy
BDD —Cl —CF3
BDE —Cl —CH2CF3
BDF —Cl —OCF3
BDG —Cl —Cl
BDH —Cl —Br
BDI —Cl —I
BDJ —Cl -n-butyl
BDK —Cl -n-propyl
BDL —F —H
BDM —F -tert-butyl
BDN —F -iso-butyl
BDO —F -sec-butyl
BDP —F -cyclohexyl
BDQ —F -tert-butoxy
BDR —F -iso-propoxy
BDS —F —CF3
BDT —F —CH2CF3
BDU —F —OCF3
BDV —F —Cl
BDW —F —Br
BDX —F —I
BDY —F -n-butyl
BDZ —F -n-propyl
BEA —CH3 —H
BEB —CH3 -tert-butyl
BEC —CH3 -iso-butyl
BED —CH3 -sec-butyl
BEE —CH3 -cyclohexyl
BEF —CH3 -tert-butoxy
BEG —CH3 -iso-propoxy
BEH —CH3 —CF3
BEI —CH3 —CH2CF3
BEJ —CH3 —OCF3
BEK —CH3 —Cl
BEL —CH3 —Br
BEM —CH3 —I
BEN —CH3 -n-butyl
BEO —CH3 -n-propyl
BEP —CF3 —H
BEQ —CF3 -tert-butyl
BER —CF3 -iso-butyl
BES —CF3 -sec-butyl
BET —CF3 -cyclohexyl
BEU —CF3 -tert-butoxy
BEV —CF3 -iso-propoxy
BEW —CF3 —CF3
BEX —CF3 —CH2CF3
BEY —CF3 —OCF3
BEZ —CF3 —Cl
BFA —CF3 —Br
BFB —CF3 —I
BFC —CF3 -n-butyl
BFD —CF3 -n-propyl
BFE —CHF2 -tert-butyl
BFF —CHF2 —H
BFG —CHF2 -iso-butyl
BFH —CHF2 -sec-butyl
BFI —CHF2 -cyclohexyl
BFJ —CHF2 -tert-butoxy
BFK —CHF2 -iso-propoxy
BFL —CHF2 —CF3
BFM —CHF2 —CH2CF3
BFN —CHF2 —OCF3
BFO —CHF2 —Cl
BFP —CHF2 —Br
BFQ —CHF2 —I
BFR —CHF2 -n-butyl
BFS —CHF2 -n-propyl
BFT —OH —H
BFU —OH -tert-butyl
BFV —OH -iso-butyl
BFW —OH -sec-butyl
BFX —OH -cyclohexyl
BFY —OH -tert-butoxy
BFZ —OH -iso-propoxy
BGA —OH —CF3
BGB —OH —CH2CF3
BGC —OH —OCF3
BGD —OH —Cl
BGE —OH —Br
BGF —OH —I
BGG —OH -n-butyl
BGH —OH -n-propyl
BGI —NO2 —H
BGJ —NO2 -tert-butyl
BGK —NO2 -iso-butyl
BGL —NO2 -sec-butyl
BGM —NO2 -cyclohexyl
BGN —NO2 -tert-butoxy
BGO —NO2 -iso-propoxy
BGP —NO2 —CF3
BGQ —NO2 —CH2CF3
BGR —NO2 —OCF3
BGS —NO2 —Cl
BGT —NO2 —Br
BGU —NO2 —I
BGV —NO2 -n-butyl
BGW —NO2 -n-propyl
BGX —CN —H
BGY —CN -tert-butyl
BGZ —CN -iso-butyl
BHA —CN -sec-butyl
BHB —CN -cyclohexyl
BHC —CN -tert-butoxy
BHD —CN -iso-propoxy
BHE —CN —CF3
BHF —CN —CH2CF3
BHG —CN —OCF3
BHH —CN —Cl
BHI —CN —Br
BHJ —CN —I
BHK —CN -n-butyl
BHL —CN -n-propyl
BHM —Br —H
BHN —Br -tert-butyl
BHO —Br -iso-butyl
BHP —Br -sec-butyl
BHQ —Br -cyclohexyl
BHR —Br -tert-butoxy
BHS —Br -iso-propoxy
BHT —Br —CF3
BHU —Br —CH2CF3
BHV —Br —OCF3
BHW —Br —Cl
BHX —Br —Br
BHY —Br —I
BHZ —Br -n-butyl
BIA —Br -n-propyl
BIB —I -tert-butyl
BIC —I —H
BID —I -iso-butyl
BIE —I -sec-butyl
BIF —I -cyclohexyl
BIG —I -tert-butoxy
BIH —I -iso-propoxy
BII —I —CF3
BIJ —I —CH2CF3
BIK —I —OCF3
BIL —I —Cl
BIM —I —Br
BlN —I —I
BIO —I -n-butyl
BIP —I -n-propyl

TABLE 7
(IIg)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
BIQ —Cl —H
BIR —Cl -tert-butyl
BIS —Cl -iso-butyl
BIT —Cl -sec-butyl
BIU —Cl -cyclohexyl
BIV —Cl -tert-butoxy
BIW —Cl -iso-propoxy
BIX —Cl —CF3
BIY —Cl —CH2CF3
BIZ —Cl —OCF3
BJA —Cl —Cl
BJB —Cl —Br
BJC —Cl —I
BJD —Cl -n-butyl
BJE —Cl -n-propyl
BJF —F —H
BJG —F -tert-butyl
BJH —F -iso-butyl
BJI —F -sec-butyl
BJJ —F -cyclohexyl
BJK —F -tert-butoxy
BJL —F -iso-propoxy
BJM —F —CF3
BJN —F —CH2CF3
BJO —F —OCF3
BJP —F —Cl
BJQ —F —Br
BJR —F —I
BJS —F -n-butyl
BJT —F -n-propyl
BJU —CH3 —H
BJV —CH3 -tert-butyl
BJW —CH3 -iso-butyl
BJX —CH3 -sec-butyl
BJY —CH3 -cyclohexyl
BJZ —CH3 -tert-butoxy
BKA —CH3 -iso-propoxy
BKB —CH3 —CF3
BKC —CH3 —CH2CF3
BKD —CH3 —OCF3
BKE —CH3 —Cl
BKF —CH3 —Br
BKG —CH3 —I
BKH —CH3 -n-butyl
BKI —CH3 -n-propyl
BKJ —CF3 —H
BKK —CF3 -tert-butyl
BKL —CF3 -iso-butyl
BKM —CF3 -sec-butyl
BKN —CF3 -cyclohexyl
BKO —CF3 -tert-butoxy
BKP —CF3 -iso-propoxy
BKQ —CF3 —CF3
BKR —CF3 —CH2CF3
BKS —CF3 —OCF3
BKT —CF3 —Cl
BKU —CF3 —Br
BKV —CF3 —I
BKW —CF3 -n-butyl
BKX —CF3 -n-propyl
BKY —CHF2 -tert-butyl
BKZ —CHF2 —H
BLA —CHF2 -iso-butyl
BLB —CHF2 -sec-butyl
BLC —CHF2 -cyclohexyl
BLD —CHF2 -tert-butoxy
BLE —CHF2 -iso-propoxy
BLF —CHF2 —CF3
BLG —CHF2 —CH2CF3
BLH —CHF2 —OCF3
BLI —CHF2 —Cl
BLJ —CHF2 —Br
BLK —CHF2 —I
BLL —CHF2 -n-butyl
BLM —CHF2 -n-propyl
BLN —OH —H
BLO —OH -tert-butyl
BLP —OH -iso-butyl
BLQ —OH -sec-butyl
BLR —OH -cyclohexyl
BLS —OH -tert-butoxy
BLT —OH -iso-propoxy
BLU —OH —CF3
BLV —OH —CH2CF3
BLW —OH —OCF3
BLX —OH —Cl
BLY —OH —Br
BLZ —OH —I
BMA —OH -n-butyl
BMB —OH -n-propyl
BMC —NO2 —H
BMD —NO2 -tert-butyl
BME —NO2 -iso-butyl
BMF —NO2 -sec-butyl
BMG —NO2 -cyclohexyl
BMH —NO2 -tert-butoxy
BMI —NO2 -iso-propoxy
BMJ —NO2 —CF3
BMK —NO2 —CH2CF3
BML —NO2 —OCF3
BMM —NO2 —Cl
BMN —NO2 —Br
BMO —NO2 —I
BMP —NO2 -n-butyl
BMQ —NO2 -n-propyl
BMR —CN —H
BMS —CN -tert-butyl
BMT —CN -iso-butyl
BMU —CN -sec-butyl
BMV —CN -cyclohexyl
BMW —CN -tert-butoxy
BMX —CN -iso-propoxy
BMY —CN —CF3
BMZ —CN —CH2CF3
BNA —CN —OCF3
BNB —CN —Cl
BNC —CN —Br
BND —CN —I
BNE —CN -n-butyl
BNF —CN -n-propyl
BNG —Br —H
BNH —Br -tert-butyl
BNI —Br -iso-butyl
BNJ —Br -sec-butyl
BNK —Br -cyclohexyl
BNL —Br -tert-butoxy
BNM —Br -iso-propoxy
BNN —Br —CF3
BNO —Br —CH2CF3
BNP —Br —OCF3
BNQ —Br —Cl
BNR —Br —Br
BNS —Br —I
BNT —Br -n-butyl
BNU —Br -n-propyl
BNV —I -tert-butyl
BNW —I —H
BNX —I -iso-butyl
BNY —I -sec-butyl
BNZ —I -cyclohexyl
BOA —I -tert-butoxy
BOB —I -iso-propoxy
BOC —I —CF3
BOD —I —CH2CF3
BOE —I —OCF3
BOF —I —Cl
BOG —I —Br
BOH —I —I
BOI —I -n-butyl
BOJ —I -n-propyl

TABLE 8
(Ih)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
BOK —Cl —H
BOL —Cl -tert-butyl
BOM —Cl -iso-butyl
BON —Cl -sec-butyl
BOO —Cl -cyclohexyl
BOP —Cl -tert-butoxy
BOQ —Cl -iso-propoxy
BOR —Cl —CF3
BOS —Cl —CH2CF3
BOT —Cl —OCF3
BOU —Cl —Cl
BOV —Cl —Br
BOW —Cl —I
BOX —Cl -n-butyl
BOY —Cl -n-propyl
BOZ —F —H
BPA —F -tert-butyl
BPB —F -iso-butyl
BPC —F -sec-butyl
BPD —F -cyclohexyl
BPE —F -tert-butoxy
BPF —F -iso-propoxy
BPG —F —CF3
BPH —F —CH2CF3
BPI —F —OCF3
BPJ —F —Cl
BPK —F —Br
BPL —F —I
BPM —F -n-butyl
BPN —F -n-propyl
BPO —CH3 —H
BPP —CH3 -tert-butyl
BPQ —CH3 -iso-butyl
BPR —CH3 -sec-butyl
BPS —CH3 -cyclohexyl
BPT —CH3 -tert-butoxy
BPU —CH3 -iso-propoxy
BPV —CH3 —CF3
BPW —CH3 —CH2CF3
BPX —CH3 —OCF3
BPY —CH3 —Cl
BPZ —CH3 —Br
BQA —CH3 —I
BQB —CH3 -n-butyl
BQC —CH3 -n-propyl
BQD —CF3 —H
BQE —CF3 -tert-butyl
BQF —CF3 -iso-butyl
BQG —CF3 -sec-butyl
BQH —CF3 -cyclohexyl
BQI —CF3 -tert-butoxy
BQJ —CF3 -iso-propoxy
BQK —CF3 —CF3
BQL —CF3 —CH2CF3
BQM —CF3 —OCF3
BQN —CF3 —Cl
BQO —CF3 —Br
BQP —CF3 —I
BQQ —CF3 -n-butyl
BQR —CF3 -n-propyl
BQS —CHF2 -tert-butyl
BQT —CHF2 —H
BQU —CHF2 -iso-butyl
BQV —CHF2 -sec-butyl
BQW —CHF2 -cyclohexyl
BQX —CHF2 -tert-butoxy
BQY —CHF2 -iso-propoxy
BQZ —CHF2 —CF3
BRA —CHF2 —CH2CF3
BRB —CHF2 —OCF3
BRC —CHF2 —Cl
BRD —CHF2 —Br
BRE —CHF2 —I
BRF —CHF2 -n-butyl
BRG —CHF2 -n-propyl
BRH —OH —H
BRI —OH -tert-butyl
BRJ —OH -iso-butyl
BRK —OH -sec-butyl
BRL —OH -cyclohexyl
BRM —OH -tert-butoxy
BRN —OH -iso-propoxy
BRO —OH —CF3
BRP —OH —CH2CF3
BRQ —OH —OCF3
BRR —OH —Cl
BRS —OH —Br
BRT —OH —I
BRU —OH -n-butyl
BRV —OH -n-propyl
BRW —NO2 —H
BRX —NO2 -tert-butyl
BRY —NO2 -iso-butyl
BRZ —NO2 -sec-butyl
BSA —NO2 -cyclohexyl
BSB —NO2 -tert-butoxy
BSC —NO2 -iso-propoxy
BSD —NO2 —CF3
BSE —NO2 —CH2CF3
BSF —NO2 —OCF3
BSG —NO2 —Cl
BSH —NO2 —Br
BSI —NO2 —I
BSJ —NO2 -n-butyl
BSK —NO2 -n-propyl
BSL —CN —H
BSM —CN -tert-butyl
BSN —CN -iso-butyl
BSO —CN -sec-butyl
BSP —CN -cyclohexyl
BSQ —CN -tert-butoxy
BSR —CN -iso-propoxy
BSS —CN —CF3
BST —CN —CH2CF3
BSU —CN —OCF3
BSV —CN —Cl
BSW —CN —Br
BSX —CN —I
BSY —CN -n-butyl
BSZ —CN -n-propyl
BTA —Br —H
BTB —Br -tert-butyl
BTC —Br -iso-butyl
BTD —Br -sec-butyl
BTE —Br -cyclohexyl
BTF —Br -tert-butoxy
BTG —Br -iso-propoxy
BTH —Br —CF3
BTI —Br —CH2CF3
BTJ —Br —OCF3
BTK —Br —Cl
BTL —Br —Br
BTM —Br —I
BTN —Br -n-butyl
BTO —Br -n-propyl
BTP —I -tert-butyl
BTQ —I —H
BTR —I -iso-butyl
BTS —I -sec-butyl
BTT —I -cyclohexyl
BTU —I -tert-butoxy
BTV —I -iso-propoxy
BTW —I —CF3
BTX —I —CH2CF3
BTY —I —OCF3
BTZ —I —Cl
BUA —I —Br
BUB —I —I
BUC —I -n-butyl
BUD —I -n-propyl

TABLE 9
(IIi)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R9
BUE —Cl —H
BUF —Cl -tert-butyl
BUG —Cl -iso-butyl
BUH —Cl -sec-butyl
BUI —Cl -cyclohexyl
BUJ —Cl -tert-butoxy
BUK —Cl -iso-propoxy
BUL —Cl —CF3
BUM —Cl —CH2CF3
BUN —Cl —OCF3
BUO —Cl —Cl
BUP —Cl —Br
BUQ —Cl —I
BUR —Cl -n-butyl
BUS —Cl -n-propyl
BUT —F —H
BUU —F -tert-butyl
BUV —F -iso-butyl
BUW —F -sec-butyl
BUX —F -cyclohexyl
BUY —F -tert-butoxy
BUZ —F -iso-propoxy
BVA —F —CF3
BVB —F —CH2CF3
BVC —F —OCF3
BVD —F —Cl
BVE —F —Br
BVF —F —I
BVG —F -n-butyl
BVH —F -n-propyl
BVI —CH3 —H
BVJ —CH3 -tert-butyl
BVK —CH3 -iso-butyl
BVL —CH3 -sec-butyl
BVM —CH3 -cyclohexyl
BVN —CH3 -tert-butoxy
BVO —CH3 -iso-propoxy
BVP —CH3 —CF3
BVQ —CH3 —CH2CF3
BVR —CH3 —OCF3
BVS —CH3 —Cl
BVT —CH3 —Br
BVU —CH3 —I
BVV —CH3 -n-butyl
BVW —CH3 -n-propyl
BVX —CF3 —H
BVY —CF3 -tert-butyl
BVZ —CF3 -iso-butyl
BWA —CF3 -sec-butyl
BWB —CF3 -cyclohexyl
BWC —CF3 -tert-butoxy
BWD —CF3 -iso-propoxy
BWE —CF3 —CF3
BWF —CF3 —CH2CF3
BWG —CF3 —OCF3
BWH —CF3 —Cl
BWI —CF3 —Br
BWJ —CF3 —I
BWK —CF3 -n-butyl
BWL —CF3 -n-propyl
BWM —CHF2 -tert-butyl
BWN —CHF2 —H
BWO —CHF2 -iso-butyl
BWP —CHF2 -sec-butyl
BWQ —CHF2 -cyclohexyl
BWR —CHF2 -tert-butoxy
BWS —CHF2 -iso-propoxy
BWT —CHF2 —CF3
BWU —CHF2 —CH2CF3
BWV —CHF2 —OCF3
BWW —CHF2 —Cl
BWX —CHF2 —Br
BWY —CHF2 —I
BWZ —CHF2 -n-butyl
BXA —CHF2 -n-propyl
BXB —OH —H
BXC —OH -tert-butyl
BXD —OH -iso-butyl
BXE —OH -sec-butyl
BXF —OH -cyclohexyl
BXG —OH -tert-butoxy
BXH —OH -iso-propoxy
BXI —OH —CF3
BXJ —OH —CH2CF3
BXK —OH —OCF3
BXL —OH —Cl
BXM —OH —Br
BXN —OH —I
BXO —OH -n-butyl
BXP —OH -n-propyl
BXQ —NO2 —H
BXR —NO2 -tert-butyl
BXS —NO2 -iso-butyl
BXT —NO2 -sec-butyl
BXU —NO2 -cyclohexyl
BXV —NO2 -tert-butoxy
BXW —NO2 -iso-propoxy
BXX —NO2 —CF3
BXY —NO2 —CH2CF3
BXZ —NO2 —OCF3
BYA —NO2 —Cl
BYB —NO2 —Br
BYC —NO2 —I
BYD —NO2 -n-butyl
BYE —NO2 -n-propyl
BYF —CN —H
BYG —CN -tert-butyl
BYH —CN -iso-butyl
BYI —CN -sec-butyl
BYJ —CN -cyclohexyl
BYK —CN -tert-butoxy
BYL —CN -iso-propoxy
BYM —CN —CF3
BYN —CN —CH2CF3
BYO —CN —OCF3
BYP —CN —Cl
BYQ —CN —Br
BYR —CN —I
BYS —CN -n-butyl
BYT —CN -n-propyl
BYU —Br —H
BYV —Br -tert-butyl
BYW —Br -iso-butyl
BYX —Br -sec-butyl
BYY —Br -cyclohexyl
BYZ —Br -tert-butoxy
BZA —Br -iso-propoxy
BZB —Br —CF3
BZC —Br —CH2CF3
BZD —Br —OCF3
BZE —Br —Cl
BZF —Br —Br
BZG —Br —I
BZH —Br -n-butyl
BZI —Br -n-propyl
BZJ —I -tert-butyl
BZK —I —H
BZL —I -iso-butyl
BZM —I -sec-butyl
BZN —I -cyclohexyl
BZO —I -tert-butoxy
BZP —I -iso-propoxy
BZQ —I —CF3
BZR —I —CH2CF3
BZS —I —OCF3
BZT —I —Cl
BZU —I —Br
BZV —I —I
BZW —I -n-butyl
BZX —I -n-propyl

TABLE 10
(Ia)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R8 R9
BZY —Cl —Cl —H
BZZ —Cl —Br —H
CAA —Cl —F —H
CAB —Cl —CH3 —H
CAC —Cl —CF3 —H
CAD —Cl —OCH3 —H
CAE —Cl —OCH2CH3 —H
CAF —Cl —OCF3 —H
CAG —Cl -tert-butyl —H
CAH —Cl -iso-propyl —H
CAI —Cl —CH3 —CH3
CAJ —Cl —H —H
CAK —Cl —H —CH3
CAL —Cl —H —CF3
CAM —Cl —H —OCH3
CAN —Cl —H —OCH2CH3
CAO —Cl —H —OCF3
CAP —Cl —H -tert-butyl
CAQ —Cl —H -iso-propyl
CAR —Cl —H —OCF3
CAS —Cl —H -tert-butyl
CAT —Cl —H -iso-propyl
CAU —CH3 —Cl —H
CAV —CH3 —Br —H
CAW —CH3 —F —H
CAX —CH3 —CH3 —H
CAY —CH3 —CF3 —H
CAZ —CH3 —OCH3 —H
CBA —CH3 —OCH2CH3 —H
CBB —CH3 —OCF3 —H
CBC —CH3 -tert-butyl —H
CBD —CH3 -iso-propyl —H
CBE —CH3 —CH3 —CH3
CBF —CH3 —H —H
CBG —CH3 —H —Cl
CBH —CH3 —H —Br
CBI —CH3 —H —F
CBJ —CH3 —H —CH3
CBK —CH3 —H —CF3
CBL —CH3 —H —OCH3
CBM —CH3 —H —OCH2CH3
CBN —CH3 —H —OCF3
CBO —CH3 —H -tert-butyl
CBP —CH3 —H -iso-propyl
CBQ —CF3 —Cl —H
CBR —CF3 —Br —H
CBS —CF3 —F —H
CBT —CF3 —CH3 —H
CBU —CF3 —CF3 —H
CBV —CF3 —OCH3 —H
CBW —CF3 —OCH2CH3 —H
CBX —CF3 —OCF3 —H
CBY —CF3 -tert-butyl —H
CBZ —CF3 -iso-propyl —H
CCA —CF3 —CH3 —CH3
CCB —CF3 —H —H
CCC —CF3 —H —Cl
CCD —CF3 —H —Br
CCE —CF3 —H —F
CCF —CF3 —H —CH3
CCG —CF3 —H —CF3
CCH —CF3 —H —OCH3
CCI —CF3 —H —OCH2CH3
CCJ —CF3 —H —OCF3
CCK —CF3 —H -tert-butyl
CCL —CF3 —H -iso-propyl
CCM —CHF2 —Cl —H
CCN —CHF2 —Br —H
CCO —CHF2 —F —H
CCP —CHF2 —CH3 —H
CCQ —CHF2 —CF3 —H
CCR —CHF2 —OCH3 —H
CCS —CHF2 —OCH2CH3 —H
CCT —CHF2 —OCF3 —H
CCU —CHF2 -tert-butyl —H
CCV —CHF2 -iso-propyl —H
CCW —CHF2 —CH3 —CH3
CCX —CHF2 —H —H
CCY —CHF2 —H —Cl
CCZ —CHF2 —H —Br
CDA —CHF2 —H —F
CDB —CHF2 —H —CH3
CDC —CHF2 —H —CF3
CDD —CHF2 —H —OCH3
CDE —CHF2 —H —OCH2CH3
CDF —CHF2 —H —OCF3
CDG —CHF2 —H -tert-butyl
CDH —CHF2 —H -iso-propyl
CDI —OH —Cl —H
CDJ —OH —Br —H
CDK —OH —F —H
CDL —OH —CH3 —H
CDM —OH —CF3 —H
CDN —OH —OCH3 —H
CDO —OH —OCH2CH3 —H
CDP —OH —OCF3 —H
CDQ —OH -tert-butyl —H
CDR —OH -iso-propyl —H
CDS —OH —CH3 —CH3
CDT —OH —H —H
CDU —OH —H —Cl
CDV —OH —H —Br
CDW —OH —H —F
CDX —OH —H —CH3
CDY —OH —H —CF3
CDZ —OH —H —OCH3
CEA —OH —H —OCH2CH3
CEB —OH —H —OCF3
CEC —OH —H -tert-butyl
CED —OH —H -iso-propyl
CEE —NO2 —Cl —H
CEF —NO2 —Br —H
CEG —NO2 —F —H
CEH —NO2 —CH3 —H
CEI —NO2 —CF3 —H
CEJ —NO2 —OCH3 —H
CEK —NO2 —OCH2CH3 —H
CEL —NO2 —OCF3 —H
CEM —NO2 -tert-butyl —H
CEN —NO2 -iso-propyl —H
CEO —NO2 —CH3 —CH3
CEP —NO2 —H —H
CEQ —NO2 —H —Cl
CER —NO2 —H —Br
CES —NO2 —H —F
CET —NO2 —H —CH3
CEU —NO2 —H —CF3
CEV —NO2 —H —OCH3
CEW —NO2 —H —OCH2CH3
CEX —NO2 —H —OCF3
CEY —NO2 —H -tert-butyl
CEZ —NO2 —H -iso-propyl
CFA —CN —Br —H
CFB —CN —Cl —H
CFC —CN —F —H
CFD —CN —CH3 —H
CFE —CN —CF3 —H
CFF —CN —OCH3 —H
CFG —CN —OCH2CH3 —H
CFH —CN —OCF3 —H
CFI —CN -tert-butyl —H
CFJ —CN -iso-propyl —H
CFK —CN —CH3 —CH3
CFL —CN —H —H
CFM —CN —H —Cl
CFN —CN —H —Br
CFO —CN —H —F
CFP —CN —H —CH3
CFQ —CN —H —CF3
CFR —CN —H —OCH3
CFS —CN —H —OCH2CH3
CFT —CN —H —OCF3
CFU —CN —H -tert-butyl
CFV —CN —H -iso-propyl
CFW —Br —Br —H
CFX —Br —Cl —H
CFY —Br —F —H
CFZ —Br —CH3 —H
CGA —Br —CF3 —H
CGB —Br —OCH3 —H
CGC —Br —OCH2CH3 —H
CGD —Br —OCF3 —H
CGE —Br -tert-butyl —H
CGF —Br -iso-propyl —H
CGG —Br —CH3 —CH3
CGH —Br —H —H
CGI —Br —H —Cl
CGJ —Br —H —Br
CGK —Br —H —F
CGL —Br —H —CH3
CGM —Br —H —CF3
CGN —Br —H —OCH3
CGO —Br —H —OCH2CH3
CGP —Br —H —OCF3
CGQ —Br —H -tert-butyl
CGR —Br —H -iso-propyl
CGS —I —Cl —H
CGT —I —Br —H
CGU —I —F —H
CGV —I —CH3 —H
CGW —I —CF3 —H
CGX —I —OCH3 —H
CGY —I —OCH2CH3 —H
CGZ —I —OCF3 —H
CHA —I -tert-butyl —H
CHB —I -iso-propyl —H
CHC —I —CH3 —CH3
CHD —I —H —H
CHE —I —H —Cl
CHF —I —H —Br
CHG —I —H —F
CHH —I —H —CH3
CHI —I —H —CF3
CHJ —I —H —OCH3
CHK —I —H —OCH2CH3
CHL —I —H —OCF3
CHM —I —H -tert-butyl
CHN —I —H -iso-propyl

TABLE 11
(Ib)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R8 R9
CHO —Cl —Cl —H
CHP —Cl —Br —H
CHQ —Cl —F —H
CHR —Cl —CH3 —H
CHS —Cl —CF3 —H
CHT —Cl —OCH3 —H
CHU —Cl —OCH2CH3 —H
CHV —Cl —OCF3 —H
CHW —Cl -tert-butyl —H
CHX —Cl -iso-propyl —H
CHY —Cl —CH3 —CH3
CHZ —Cl —H —H
CIA —Cl —H —CH3
CIB —Cl —H —CF3
CIC —Cl —H —OCH3
CID —Cl —H —OCH2CH3
CIE —Cl —H —OCF3
CIF —Cl —H -tert-butyl
CIG —Cl —H -iso-propyl
CIH —Cl —H —OCF3
CII —Cl —H -tert-butyl
CIJ —Cl —H -iso-propyl
CIK —CH3 —Cl —H
CIL —CH3 —Br —H
CIM —CH3 —F —H
CIN —CH3 —CH3 —H
CIO —CH3 —CF3 —H
CIP —CH3 —OCH3 —H
CIQ —CH3 —OCH2CH3 —H
CIR —CH3 —OCF3 —H
CIS —CH3 -tert-butyl —H
CIT —CH3 -iso-propyl —H
CIU —CH3 —CH3 —CH3
CIV —CH3 —H —H
CIW —CH3 —H —Cl
CIX —CH3 —H —Br
CIY —CH3 —H —F
CIZ —CH3 —H —CH3
CJA —CH3 —H —CF3
CJB —CH3 —H —OCH3
CJC —CH3 —H —OCH2CH3
CJD —CH3 —H —OCF3
CJE —CH3 —H -tert-butyl
CJF —CH3 —H -iso-propyl
CJG —CF3 —Cl —H
CJH —CF3 —Br —H
CJI —CF3 —F —H
CJJ —CF3 —CH3 —H
CJK —CF3 —CF3 —H
CJL —CF3 —OCH3 —H
CJM —CF3 —OCH2CH3 —H
CJN —CF3 —OCF3 —H
CJO —CF3 -tert-butyl —H
CJP —CF3 -iso-propyl —H
CJQ —CF3 —CH3 —CH3
CJR —CF3 —H —H
CJS —CF3 —H —Cl
CJT —CF3 —H —Br
CJU —CF3 —H —F
CJV —CF3 —H —CH3
CJW —CF3 —H —CF3
CJX —CF3 —H —OCH3
CJY —CF3 —H —OCH2CH3
CJZ —CF3 —H —OCF3
CKA —CF3 —H -tert-butyl
CKB —CF3 —H -iso-propyl
CKC —CHF2 —Cl —H
CKD —CHF2 —Br —H
CKE —CHF2 —F —H
CKF —CHF2 —CH3 —H
CKG —CHF2 —CF3 —H
CKH —CHF2 —OCH3 —H
CKI —CHF2 —OCH2CH3 —H
CKJ —CHF2 —OCF3 —H
CKK —CHF2 -tert-butyl —H
CKL —CHF2 -iso-propyl —H
CKM —CHF2 —CH3 —CH3
CKN —CHF2 —H —H
CKO —CHF2 —H —Cl
CKP —CHF2 —H —Br
CKQ —CHF2 —H —F
CKR —CHF2 —H —CH3
CKS —CHF2 —H —CF3
CKT —CHF2 —H —OCH3
CKU —CHF2 —H —OCH2CH3
CKV —CHF2 —H —OCF3
CKW —CHF2 —H -tert-butyl
CKX —CHF2 —H -iso-propyl
CKY —OH —Cl —H
CKZ —OH —Br —H
CLA —OH —F —H
CLB —OH —CH3 —H
CLC —OH —CF3 —H
CLD —OH —OCH3 —H
CLE —OH —OCH2CH3 —H
CLF —OH —OCF3 —H
CLG —OH -tert-butyl —H
CLH —OH -iso-propyl —H
CLI —OH —CH3 —CH3
CLJ —OH —H —H
CLK —OH —H —Cl
CLL —OH —H —Br
CLM —OH —H —F
CLN —OH —H —CH3
CLO —OH —H —CF3
CLP —OH —H —OCH3
CLQ —OH —H —OCH2CH3
CLR —OH —H —OCF3
CLS —OH —H -tert-butyl
CLT —OH —H -iso-propyl
CLU —NO2 —Cl —H
CLV —NO2 —Br —H
CLW —NO2 —F —H
CLX —NO2 —CH3 —H
CLY —NO2 —CF3 —H
CLZ —NO2 —OCH3 —H
CMA —NO2 —OCH2CH3 —H
CMB —NO2 —OCF3 —H
CMC —NO2 -tert-butyl —H
CMD —NO2 -iso-propyl —H
CME —NO2 —CH3 —CH3
CMF —NO2 —H —H
CMG —NO2 —H —Cl
CMH —NO2 —H —Br
CMI —NO2 —H —F
CMJ —NO2 —H —CH3
CMK —NO2 —H —CF3
CML —NO2 —H —OCH3
CMM —NO2 —H —OCH2CH3
CMN —NO2 —H —OCF3
CMO —NO2 —H -tert-butyl
CMP —NO2 —H -iso-propyl
CMQ —CN —Br —H
CMR —CN —Cl —H
CMS —CN —F —H
CMT —CN —CH3 —H
CMU —CN —CF3 —H
CMV —CN —OCH3 —H
CMW —CN —OCH2CH3 —H
CMX —CN —OCF3 —H
CMY —CN -tert-butyl —H
CMZ —CN -iso-propyl —H
CNA —CN —CH3 —CH3
CNB —CN —H —H
CNC —CN —H —Cl
CND —CN —H —Br
CNE —CN —H —F
CNF —CN —H —CH3
CNG —CN —H —CF3
CNH —CN —H —OCH3
CNI —CN —H —OCH2CH3
CNJ —CN —H —OCF3
CNK —CN —H -tert-butyl
CNL —CN —H -iso-propyl
CNM —Br —Br —H
CNN —Br —Cl —H
CNO —Br —F —H
CNP —Br —CH3 —H
CNQ —Br —CF3 —H
CNR —Br —OCH3 —H
CNS —Br —OCH2CH3 —H
CNT —Br —OCF3 —H
CNU —Br -tert-butyl —H
CNV —Br -iso-propyl —H
CNW —Br —CH3 —CH3
CNX —Br —H —H
CNY —Br —H —Cl
CNZ —Br —H —Br
COA —Br —H —F
COB —Br —H —CH3
COC —Br —H —CF3
COD —Br —H —OCH3
COE —Br —H —OCH2CH3
COF —Br —H —OCF3
COG —Br —H -tert-butyl
COH —Br —H -iso-propyl
COI —I —Cl —H
COJ —I —Br —H
COK —I —F —H
COL —I —CH3 —H
COM —I —CF3 —H
CON —I —OCH3 —H
COO —I —OCH2CH3 —H
COP —I —OCF3 —H
COQ —I -tert-butyl —H
COR —I -iso-propyl —H
COS —I —CH3 —CH3
COT —I —H —H
COU —I —H —Cl
COV —I —H —Br
COW —I —H —F
COX —I —H —CH3
COY —I —H —CF3
COZ —I —H —OCH3
CPA —I —H —OCH2CH3
CPB —I —H —OCF3
CPC —I —H -tert-butyl
CPD —I —H -iso-propyl

TABLE 12
(Ic)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R8 R9
CPE —Cl —Cl —H
CPF —Cl —Br —H
CPG —Cl —F —H
CPH —Cl —CH3 —H
CPI —Cl —CF3 —H
CPJ —Cl —OCH3 —H
CPK —Cl —OCH2CH3 —H
CPL —Cl —OCF3 —H
CPM —Cl -tert-butyl —H
CPN —Cl -iso-propyl —H
CPO —Cl —CH3 —CH3
CPP —Cl —H —H
CPQ —Cl —H —CH3
CPR —Cl —H —CF3
CPS —Cl —H —OCH3
CPT —Cl —H —OCH2CH3
CPU —Cl —H —OCF3
CPV —Cl —H -tert-butyl
CPW —Cl —H -iso-propyl
CPX —Cl —H —OCF3
CPY —Cl —H -tert-butyl
CPZ —Cl —H -iso-propyl
CQA —CH3 —Cl —H
CQB —CH3 —Br —H
CQC —CH3 —F —H
CQD —CH3 —CH3 —H
CQE —CH3 —CF3 —H
CQF —CH3 —OCH3 —H
CQG —CH3 —OCH2CH3 —H
CQH —CH3 —OCF3 —H
CQI —CH3 -tert-butyl —H
CQJ —CH3 -iso-propyl —H
CQK —CH3 —CH3 —CH3
CQL —CH3 —H —H
CQM —CH3 —H —Cl
CQN —CH3 —H —Br
CQO —CH3 —H —F
CQP —CH3 —H —CH3
CQQ —CH3 —H —CF3
CQR —CH3 —H —OCH3
CQS —CH3 —H —OCH2CH3
CQT —CH3 —H —OCF3
CQU —CH3 —H -tert-butyl
CQV —CH3 —H -iso-propyl
CQW —CF3 —Cl —H
CQX —CF3 —Br —H
CQY —CF3 —F —H
CQZ —CF3 —CH3 —H
CRA —CF3 —CF3 —H
CRB —CF3 —OCH3 —H
CRC —CF3 —OCH2CH3 —H
CRD —CF3 —OCF3 —H
CRE —CF3 -tert-butyl —H
CRF —CF3 -iso-propyl —H
CRG —CF3 —CH3 —CH3
CRH —CF3 —H —H
CRI —CF3 —H —Cl
CRJ —CF3 —H —Br
CRK —CF3 —H —F
CRL —CF3 —H —CH3
CRM —CF3 —H —CF3
CRN —CF3 —H —OCH3
CRO —CF3 —H —OCH2CH3
CRP —CF3 —H —OCF3
CRQ —CF3 —H -tert-butyl
CRR —CF3 —H -iso-propyl
CRS —CHF2 —Cl —H
CRT —CHF2 —Br —H
CRU —CHF2 —F —H
CRV —CHF2 —CH3 —H
CRW —CHF2 —CF3 —H
CRX —CHF2 —OCH3 —H
CRY —CHF2 —OCH2CH3 —H
CRZ —CHF2 —OCF3 —H
CSA —CHF2 -tert-butyl —H
CSB —CHF2 -iso-propyl —H
CSC —CHF2 —CH3 —CH3
CSD —CHF2 —H —H
CSE —CHF2 —H —Cl
CSF —CHF2 —H —Br
CSG —CHF2 —H —F
CSH —CHF2 —H —CH3
CSI —CHF2 —H —CF3
CSJ —CHF2 —H —OCH3
CSK —CHF2 —H —OCH2CH3
CSL —CHF2 —H —OCF3
CSM —CHF2 —H -tert-butyl
CSN —CHF2 —H -iso-propyl
CSO —OH —Cl —H
CSP —OH —Br —H
CSQ —OH —F —H
CSR —OH —CH3 —H
CSS —OH —CF3 —H
CST —OH —OCH3 —H
CSU —OH —OCH2CH3 —H
CSV —OH —OCF3 —H
CSW —OH -tert-butyl —H
CSX —OH -iso-propyl —H
CSY —OH —CH3 —CH3
CSZ —OH —H —H
CTA —OH —H —Cl
CTB —OH —H —Br
CTC —OH —H —F
CTD —OH —H —CH3
CTE —OH —H —CF3
CTF —OH —H —OCH3
CTG —OH —H —OCH2CH3
CTH —OH —H —OCF3
CTI —OH —H -tert-butyl
CTJ —OH —H -iso-propyl
CTK —NO2 —Cl —H
CTL —NO2 —Br —H
CTM —NO2 —F —H
CTN —NO2 —CH3 —H
CTO —NO2 —CF3 —H
CTP —NO2 —OCH3 —H
CTQ —NO2 —OCH2CH3 —H
CTR —NO2 —OCF3 —H
CTS —NO2 -tert-butyl —H
CTT —NO2 -iso-propyl —H
CTU —NO2 —CH3 —CH3
CTV —NO2 —H —H
CTW —NO2 —H —Cl
CTX —NO2 —H —Br
CTY —NO2 —H —F
CTZ —NO2 —H —CH3
CUA —NO2 —H —CF3
CUB —NO2 —H —OCH3
CUC —NO2 —H —OCH2CH3
CUD —NO2 —H —OCF3
CUE —NO2 —H -tert-butyl
CUF —NO2 —H -iso-propyl
CUG —CN —Br —H
CUH —CN —Cl —H
CUI —CN —F —H
CUJ —CN —CH3 —H
CUK —CN —CF3 —H
CUL —CN —OCH3 —H
CUM —CN —OCH2CH3 —H
CUN —CN —OCF3 —H
CUO —CN -tert-butyl —H
CUP —CN -iso-propyl —H
CUQ —CN —CH3 —CH3
CUR —CN —H —H
CUS —CN —H —Cl
CUT —CN —H —Br
CUU —CN —H —F
CUV —CN —H —CH3
CUW —CN —H —CF3
CUX —CN —H —OCH3
CUY —CN —H —OCH2CH3
CUZ —CN —H —OCF3
CVA —CN —H -tert-butyl
CVB —CN —H -iso-propyl
CVC —Br —Br —H
CVD —Br —Cl —H
CVE —Br —F —H
CVF —Br —CH3 —H
CVG —Br —CF3 —H
CVH —Br —OCH3 —H
CVI —Br —OCH2CH3 —H
CVJ —Br —OCF3 —H
CVK —Br -tert-butyl —H
CVL —Br -iso-propyl —H
CVM —Br —CH3 —CH3
CVN —Br —H —H
CVO —Br —H —Cl
CVP —Br —H —Br
CVQ —Br —H —F
CVR —Br —H —CH3
CVS —Br —H —CF3
CVT —Br —H —OCH3
CVU —Br —H —OCH2CH3
CVV —Br —H —OCF3
CVW —Br —H -tert-butyl
CVX —Br —H -iso-propyl
CVY —I —Cl —H
CVZ —I —Br —H
CWA —I —F —H
CWB —I —CH3 —H
CWC —I —CF3 —H
CWD —I —OCH3 —H
CWE —I —OCH2CH3 —H
CWF —I —OCF3 —H
CWG —I -tert-butyl —H
CWH —I -iso-propyl —H
CWI —I —CH3 —CH3
CWJ —I —H —H
CWK —I —H —Cl
CWL —I —H —Br
CWM —I —H —F
CWN —I —H —CH3
CWO —I —H —CF3
CWP —I —H —OCH3
CWQ —I —H —OCH2CH3
CWR —I —H —OCF3
CWS —I —H -tert-butyl
CWT —I —H -iso-propyl

TABLE 13
(Id)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R8 R9
CWU —Cl —Cl —H
CWV —Cl —Br —H
CWW —Cl —F —H
CWX —Cl —CH3 —H
CWY —Cl —CF3 —H
CWZ —Cl —OCH3 —H
CXA —Cl —OCH2CH3 —H
CXB —Cl —OCF3 —H
CXC —Cl -tert-butyl —H
CXD —Cl -iso-propyl —H
CXE —Cl —CH3 —CH3
CXF —Cl —H —H
CXG —Cl —H —CH3
CXH —Cl —H —CF3
CXI —Cl —H —OCH3
CXJ —Cl —H —OCH2CH3
CXK —Cl —H —OCF3
CXL —Cl —H -tert-butyl
CXM —Cl —H -iso-propyl
CXN —Cl —H —OCF3
CXO —Cl —H -tert-butyl
CXP —Cl —H -iso-propyl
CXQ —CH3 —Cl —H
CXR —CH3 —Br —H
CXS —CH3 —F —H
CXT —CH3 —CH3 —H
CXU —CH3 —CF3 —H
CXV —CH3 —OCH3 —H
CXW —CH3 —OCH2CH3 —H
CXX —CH3 —OCF3 —H
CXY —CH3 -tert-butyl —H
CXZ —CH3 -iso-propyl —H
CYA —CH3 —CH3 —CH3
CYB —CH3 —H —H
CYC —CH3 —H —Cl
CYD —CH3 —H —Br
CYE —CH3 —H —F
CYF —CH3 —H —CH3
CYG —CH3 —H —CF3
CYH —CH3 —H —OCH3
CYI —CH3 —H —OCH2CH3
CYJ —CH3 —H —OCF3
CYK —CH3 —H -tert-butyl
CYL —CH3 —H -iso-propyl
CYM —CF3 —Cl —H
CYN —CF3 —Br —H
CYG —CF3 —F —H
CYP —CF3 —CH3 —H
CYQ —CF3 —CF3 —H
CYR —CF3 —OCH3 —H
CYS —CF3 —OCH2CH3 —H
CYT —CF3 —OCF3 —H
CYU —CF3 -tert-butyl —H
CYV —CF3 -iso-propyl —H
CYW —CF3 —CH3 —CH3
CYX —CF3 —H —H
CYY —CF3 —H —Cl
CYZ —CF3 —H —Br
CZA —CF3 —H —F
CZB —CF3 —H —CH3
CZC —CF3 —H —CF3
CZD —CF3 —H —OCH3
CZE —CF3 —H —OCH2CH3
CZF —CF3 —H —OCF3
CZG —CF3 —H -tert-butyl
CZH —CF3 —H -iso-propyl
CZI —CHF2 —Cl —H
CZJ —CHF2 —Br —H
CZK —CHF2 —F —H
CZL —CHF2 —CH3 —H
CZM —CHF2 —CF3 —H
CZN —CHF2 —OCH3 —H
CZO —CHF2 —OCH2CH3 —H
CZP —CHF2 —OCF3 —H
CZQ —CHF2 -tert-butyl —H
CZR —CHF2 -iso-propyl —H
CZS —CHF2 —CH3 —CH3
CZT —CHF2 —H —H
CZU —CHF2 —H —Cl
CZV —CHF2 —H —Br
CZW —CHF2 —H —F
CZX —CHF2 —H —CH3
CZY —CHF2 —H —CF3
CZZ —CHF2 —H —OCH3
DAA —CHF2 —H —OCH2CH3
DAB —CHF2 —H —OCF3
DAC —CHF2 —H -tert-butyl
DAD —CHF2 —H -iso-propyl
DAE —OH —Cl —H
DAF —OH —Br —H
DAG —OH —F —H
DAH —OH —CH3 —H
DAI —OH —CF3 —H
DAJ —OH —OCH3 —H
DAK —OH —OCH2CH3 —H
DAL —OH —OCF3 —H
DAM —OH -tert-butyl —H
DAN —OH -iso-propyl —H
DAO —OH —CH3 —CH3
DAP —OH —H —H
DAQ —OH —H —Cl
DAR —OH —H —Br
DAS —OH —H —F
DAT —OH —H —CH3
DAU —OH —H —CF3
DAV —OH —H —OCH3
DAW —OH —H —OCH2CH3
DAX —OH —H —OCF3
DAY —OH —H -tert-butyl
DAZ —OH —H -iso-propyl
DBA —NO2 —Cl —H
DBB —NO2 —Br —H
DBC —NO2 —F —H
DBD —NO2 —CH3 —H
DBE —NO2 —CF3 —H
DBF —NO2 —OCH3 —H
DBG —NO2 —OCH2CH3 —H
DBH —NO2 —OCF3 —H
DBI —NO2 -tert-butyl —H
DBJ —NO2 -iso-propyl —H
DBK —NO2 —CH3 —CH3
DBL —NO2 —H —H
DBM —NO2 —H —Cl
DBN —NO2 —H —Br
DBO —NO2 —H —F
DBP —NO2 —H —CH3
DBQ —NO2 —H —CF3
DBR —NO2 —H —OCH3
DBS —NO2 —H —OCH2CH3
DBT —NO2 —H —OCF3
DBU —NO2 —H -tert-butyl
DBV —NO2 —H -iso-propyl
DBW —CN —Br —H
DBX —CN —Cl —H
DBY —CN —F —H
DBZ —CN —CH3 —H
DCA —CN —CF3 —H
DCB —CN —OCH3 —H
DCC —CN —OCH2CH3 —H
DCD —CN —OCF3 —H
DCE —CN -tert-butyl —H
DCF —CN -iso-propyl —H
DCG —CN —CH3 —CH3
DCH —CN —H —H
DCI —CN —H —Cl
DCJ —CN —H —Br
DCK —CN —H —F
DCL —CN —H —CH3
DCM —CN —H —CF3
DCN —CN —H —OCH3
DCO —CN —H —OCH2CH3
DCP —CN —H —OCF3
DCQ —CN —H -tert-butyl
DCR —CN —H -iso-propyl
DCS —Br —Br —H
DCT —Br —Cl —H
DCU —Br —F —H
DCV —Br —CH3 —H
DCW —Br —CF3 —H
DCX —Br —OCH3 —H
DCY —Br —OCH2CH3 —H
DCZ —Br —OCF3 —H
DDA —Br -tert-butyl —H
DDB —Br -iso-propyl —H
DDC —Br —CH3 —CH3
DDD —Br —H —H
DDE —Br —H —Cl
DDF —Br —H —Br
DDG —Br —H —F
DDH —Br —H —CH3
DDI —Br —H —CF3
DDJ —Br —H —OCH3
DDK —Br —H —OCH2CH3
DDL —Br —H —OCF3
DDM —Br —H -tert-butyl
DDN —Br —H -iso-propyl
DDO —I —Cl —H
DDP —I —Br —H
DDQ —I —F —H
DDR —I —CH3 —H
DDS —I —CF3 —H
DDT —I —OCH3 —H
DDU —I —OCH2CH3 —H
DDV —I —OCF3 —H
DDW —I -tert-butyl —H
DDX —I -iso-propyl —H
DDY —I —CH3 —CH3
DDZ —I —H —H
DEA —I —H —Cl
DEB —I —H —Br
DEC —I —H —F
DED —I —H —CH3
DEE —I —H —CF3
DEF —I —H —OCH3
DEG —I —H —OCH2CH3
DEH —I —H —OCF3
DEI —I —H -tert-butyl
DEJ —I —H -iso-propyl

TABLE 14
(Ie)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R8 R9
DEK —Cl —Cl —H
DEL —Cl —Br —H
DEM —Cl —F —H
DEN —Cl —CH3 —H
DEO —Cl —CF3 —H
DEP —Cl —OCH3 —H
DEQ —Cl —OCH2CH3 —H
DER —Cl —OCF3 —H
DES —Cl -tert-butyl —H
DET —Cl -iso-propyl —H
DEU —Cl —CH3 —CH3
DEV —Cl —H —H
DEW —Cl —H —CH3
DEX —Cl —H —CF3
DEY —Cl —H —OCH3
DEZ —Cl —H —OCH2CH3
DFA —Cl —H —OCF3
DFB —Cl —H -tert-butyl
DFC —Cl —H -iso-propyl
DFD —Cl —H —OCF3
DFE —Cl —H -tert-butyl
DFF —Cl —H -iso-propyl
DFG —CH3 —Cl —H
DFH —CH3 —Br —H
DFI —CH3 —F —H
DFJ —CH3 —CH3 —H
DFK —CH3 —CF3 —H
DFL —CH3 —OCH3 —H
DFM —CH3 —OCH2CH3 —H
DFN —CH3 —OCF3 —H
DFO —CH3 -tert-butyl —H
DFP —CH3 -iso-propyl —H
DFQ —CH3 —CH3 —CH3
DFR —CH3 —H —H
DFS —CH3 —H —Cl
DFT —CH3 —H —Br
DFU —CH3 —H —F
DFV —CH3 —H —CH3
DFW —CH3 —H —CF3
DFX —CH3 —H —OCH3
DFY —CH3 —H —OCH2CH3
DFZ —CH3 —H —OCF3
DGA —CH3 —H -tert-butyl
DGB —CH3 —H -iso-propyl
DGC —CF3 —Cl —H
DGD —CF3 —Br —H
DGE —CF3 —F —H
DGF —CF3 —CH3 —H
DGG —CF3 —CF3 —H
DGH —CF3 —OCH3 —H
DGI —CF3 —OCH2CH3 —H
DGJ —CF3 —OCF3 —H
DGK —CF3 -tert-butyl —H
DGL —CF3 -iso-propyl —H
DGM —CF3 —CH3 —CH3
DGN —CF3 —H —H
DGO —CF3 —H —Cl
DGP —CF3 —H —Br
DGQ —CF3 —H —F
DGR —CF3 —H —CH3
DGS —CF3 —H —CF3
DGT —CF3 —H —OCH3
DGU —CF3 —H —OCH2CH3
DGV —CF3 —H —OCF3
DGW —CF3 —H -tert-butyl
DGX —CF3 —H -iso-propyl
DGY —CHF2 —Cl —H
DGZ —CHF2 —Br —H
DHA —CHF2 —F —H
DHB —CHF2 —CH3 —H
DHC —CHF2 —CF3 —H
DHD —CHF2 —OCH3 —H
DHE —CHF2 —OCH2CH3 —H
DHF —CHF2 —OCF3 —H
DHG —CHF2 -tert-butyl —H
DHH —CHF2 -iso-propyl —H
DHI —CHF2 —CH3 —CH3
DHJ —CHF2 —H —H
DHK —CHF2 —H —Cl
DHL —CHF2 —H —Br
DHM —CHF2 —H —F
DHN —CHF2 —H —CH3
DHO —CHF2 —H —CF3
DHP —CHF2 —H —OCH3
DHQ —CHF2 —H —OCH2CH3
DHR —CHF2 —H —OCF3
DHS —CHF2 —H -tert-butyl
DHT —CHF2 —H -iso-propyl
DHU —OH —Cl —H
DHV —OH —Br —H
DHW —OH —F —H
DHX —OH —CH3 —H
DHY —OH —CF3 —H
DHZ —OH —OCH3 —H
DIA —OH —OCH2CH3 —H
DIB —OH —OCF3 —H
DIC —OH -tert-butyl —H
DID —OH -iso-propyl —H
DIE —OH —CH3 —CH3
DIF —OH —H —H
DIG —OH —H —Cl
DIH —OH —H —Br
DII —OH —H —F
DIJ —OH —H —CH3
DIK —OH —H —CF3
DIL —OH —H —OCH3
DIM —OH —H —OCH2CH3
DIN —OH —H —OCF3
DIO —OH —H -tert-butyl
DIP —OH —H -iso-propyl
DIQ —NO2 —Cl —H
DIR —NO2 —Br —H
DIS —NO2 —F —H
DIT —NO2 —CH3 —H
DIU —NO2 —CF3 —H
DIV —NO2 —OCH3 —H
DIW —NO2 —OCH2CH3 —H
DIX —NO2 —OCF3 —H
DIY —NO2 -tert-butyl —H
DIZ —NO2 -iso-propyl —H
DJA —NO2 —CH3 —CH3
DJB —NO2 —H —H
DJC —NO2 —H —Cl
DJD —NO2 —H —Br
DJE —NO2 —H —F
DJF —NO2 —H —CH3
DJG —NO2 —H —CF3
DJH —NO2 —H —OCH3
DJI —NO2 —H —OCH2CH3
DJJ —NO2 —H —OCF3
DJK —NO2 —H -tert-butyl
DJL —NO2 —H -iso-propyl
DJM —CN —Br —H
DJN —CN —Cl —H
DJO —CN —F —H
DJP —CN —CH3 —H
DJQ —CN —CF3 —H
DJR —CN —OCH3 —H
DJS —CN —OCH2CH3 —H
DJT —CN —OCF3 —H
DJU —CN -tert-butyl —H
DJV —CN -iso-propyl —H
DJW —CN —CH3 —CH3
DJX —CN —H —H
DJY —CN —H —Cl
DJZ —CN —H —Br
DKA —CN —H —F
DKB —CN —H —CH3
DKC —CN —H —CF3
DKD —CN —H —OCH3
DKE —CN —H —OCH2CH3
DKF —CN —H —OCF3
DKG —CN —H -tert-butyl
DKH —CN —H -iso-propyl
DKI —Br —Br —H
DKJ —Br —Cl —H
DKK —Br —F —H
DKL —Br —CH3 —H
DKM —Br —CF3 —H
DKN —Br —OCH3 —H
DKO —Br —OCH2CH3 —H
DKP —Br —OCF3 —H
DKQ —Br -tert-butyl —H
DKR —Br -iso-propyl —H
DKS —Br —CH3 —CH3
DKT —Br —H —H
DKU —Br —H —Cl
DKV —Br —H —Br
DKW —Br —H —F
DKX —Br —H —CH3
DKY —Br —H —CF3
DKZ —Br —H —OCH3
DLA —Br —H —OCH2CH3
DLB —Br —H —OCF3
DLC —Br —H -tert-butyl
DLD —Br —H -iso-propyl
DLE —I —Cl —H
DLF —I —Br —H
DLG —I —F —H
DLH —I —CH3 —H
DLI —I —CF3 —H
DLJ —I —OCH3 —H
DLK —I —OCH2CH3 —H
DLL —I —OCF3 —H
DLM —I -tert-butyl —H
DLN —I -iso-propyl —H
DLO —I —CH3 —CH3
DLP —I —H —H
DLQ —I —H —Cl
DLR —I —H —Br
DLS —I —H —F
DLT —I —H —CH3
DLU —I —H —CF3
DLV —I —H —OCH3
DLW —I —H —OCH2CH3
DLX —I —H —OCF3
DLY —I —H -tert-butyl
DLZ —I —H -iso-propyl

TABLE 15
(If)
and pharmaceutically acceptable salts thereof, where:
Compound R1 R8 R9
DMA —Cl —Cl